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1
Sitrin, Jonathan, Lisa Marshall, Hai Tran, Kenneth Ng, Kimberly Hoi, Josef Gramespacher, Zhong Huang, et al. "Abstract 1866: Discovery of mutation-independent EGFR degrading bispecific antibodies that suppress tumor growth in preclinical tumor models." Cancer Research 84, no. 6_Supplement (March 22, 2024): 1866. http://dx.doi.org/10.1158/1538-7445.am2024-1866.
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Abstract Extracellular targeted protein degradation (eTPD) has emerged as a promising new drug modality focused on targeted elimination of extracellular and transmembrane proteins. In contrast to intracellular protein degraders, such as proteolysis targeting chimeras (PROTACs) and molecular glues which require ubiquitin-proteosome cellular degradation pathways, extracellular protein degraders can additionally harness endosomal-lysosomal protein degradation. Two recently published examples of extracellular protein degraders include AbTACs (antibody-based PROTAC) which co-engage a protein of interest (POI) and transmembrane E3 ligases, and KineTACs (cytokine receptor-targeting chimeras) which utilize endogenous cytokine receptors to degrade extracellular POIs. These bispecific antibody degrader platforms not only have advantageous pharmacological and drug-like manufacturing properties, but can also be engineered for tissue-specificity and to address multiple complementary targets, with the goal of increased efficacy and decreased toxicity. To that end, we have greatly expanded the extracellular degrader repertoire beyond AbTACs and KineTACs, with a novel bispecific antibody degrader platform called TrainTACs (tissue receptor antigen internalization targeting chimeras). To demonstrate the potential of this novel extracellular degrading platform, we developed degraders for the canonical receptor tyrosine kinase epidermal growth factor receptor (EGFR). EGFR is an oncogenic driver, that has been clinically validated in lung, colorectal and head and neck cancers, but patient benefit has been limited by treatment-related acquired resistance mutations and on-target/off-tumor dose-limiting toxicities. The potential of our TrainTACs, AbTACs and KineTACs to overcome the limitations of current therapeutic modalities was assessed. Gene expression profiles from tumor and normal tissues were evaluated to identify potential degraders co-expressed with EGFR in tumors. More than 70 unique bispecific antibody constructs spanning 20 receptors were generated and screened in tumor cell-based assays to evaluate EGFR antagonism, internalization, and degradation. TrainTACs, AbTACs and KineTACs degraded EGFR in multiple tumor cell lines covering a range of EGFR mutations. Degradation of EGFR led to deep inhibition of EGFR signaling, robust inhibitory effects on tumor spheroids, and in xenograft mouse tumor models. In conclusion, eTPD represents a promising new drug modality, and TrainTACs, AbTACs and KineTACs have expanded the toolbox of extracellular targeted protein degraders that can be utilized in a target-, tissue- and disease-specific manner. Citation Format: Jonathan Sitrin, Lisa Marshall, Hai Tran, Kenneth Ng, Kimberly Hoi, Josef Gramespacher, Zhong Huang, Andy Goodrich, Filomena Housley, May Dayao, Man-Tzu Wang, Katarina Pance, Aleysha Chen, Kevin Carlin, Lichao Zhang, James Lee, Rami Hannoush, Ken Flanagan, Maia Vinogradova, Isaac Rondon, Shyra Gardai. Discovery of mutation-independent EGFR degrading bispecific antibodies that suppress tumor growth in preclinical tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1866.
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He, Tongchen, Caleb Cheng, Abhijit Parolia, Alex Hopkins, Yuanyuan Qiao, Lanbo Xiao, and Arul Chinnaiyan. "Abstract 1685: Overcoming acquired resistance to PROTAC degraders." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1685. http://dx.doi.org/10.1158/1538-7445.am2023-1685.
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Abstract Background: Proteolysis-targeting chimera (PROTAC) technology has been widely investigated for cancer treatment and there have been several PROTAC degrader-based drugs used for clinical trials in the past few years. PROTAC degraders are able to target crucial proteins traditionally thought to be “undruggable”, such as transcriptional factors. Hence, there is increasing interest in these drugs due to their highly efficacy and low off-target toxicity. However, upon further investigation, it has been found that after a period of treatment with PROTAC degraders, cancer cells can acquire resistance to these compounds. Thus, it is of increasing importance to figure out the mechanisms of the resistance and to overcome the acquired resistance to these PROTAC degraders. In our study, we classified resistance mechanisms of prostate cancer cells to PROTAC degraders into two classes and identified factors that can induce them to preferentially develop specific resistance mechanisms. Methods and Results: AU-15330 is a PROTAC that specifically degrades the subunits (BRG1, PBRM1, BRM) of SWI/SNF complex. We treated 22rv1, a prostate cancer cell line, with different AU-15330 concentrations over a month to establish AU-15330-resistant cell lines. Whole exome sequencing (WES) analysis of these resistant cell lines found that the resistant cell lines that were developed through high-dose (1uM) AU-15330 treatment acquired multiple point mutations within or adjacent to the AU-15330 targeting bromodomain of BRG1. However, BRG1 point mutations were absent in the resistant cell lines that developed through lower concentration of AU-15330 treatment (100nM). Instead, RNA-seq analysis revealed that ABCB1 (also known as Multidrug Resistance Protein 1) expression was upregulated in cells that developed resistance to AU-15330 at 100nM. This was further confirmed by Western blot and qPCR. Next, we overexpressed ABCB1 in LNCaP and 22RV1, and found that overexpression of ABCB1 indeed made prostate cancer cells resistant to AU15330. In addition, we tested with several different potent PROTAC degraders (ARD616, ZBC260, etc) in ABCB1-expressing AU-15530 resistant cells, and found the ABCB1 expression drove the cells to become resistant to all tested PROATC degraders compared to the parental cells. Lastly, we demonstrated that Zosuquidar, an ABCB1 inhibitor, can overcome the ABCB1-mediated resistance to AU-15330 and other PROTAC degraders, suggesting that inhibiting ABCB1 might be a direct and effective strategy to restore PROTAC degrader’s potency when ABCB1-mediated drug resistance is developed. Conclusion: Our study found that the mechanisms of resistance of PROTAC degraders can vary and may be dependent on drug concentrations. Such concepts may inform future clinical decision-making regarding drug dosing. Citation Format: Tongchen He, Caleb Cheng, Abhijit Parolia, Alex Hopkins, Yuanyuan Qiao, Lanbo Xiao, Arul Chinnaiyan. Overcoming acquired resistance to PROTAC degraders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1685.
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Valinciute, Gintvile, Lorenz Eing, Jeffrey Mihalic, Colleen E. Casey, Hua Tian, Bikash Adhikari, Cristiana Guiducci, et al. "OTHR-02. CHIMERIC AURORA A KINASE (AURKA) DEGRADERS EFFICIENTLY TARGET N-MYC." Neuro-Oncology 25, Supplement_1 (June 1, 2023): i73—i74. http://dx.doi.org/10.1093/neuonc/noad073.284.
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Abstract MYC family proteins are primary drivers of oncogenic processes in a variety of cancer histologies. N-myc overexpression and amplification induce aggressive pediatric cancers, the most common of which are solid extracranial tumors in children (neuroblastoma, NB) and malignant pediatric CNS tumors (medulloblastoma, MB). Due to the oncogenic addiction observed in these tumor types, N-myc is considered an attractive therapeutic target. However, direct small molecule targeting of N-myc remains technically challenging. Alternative approaches to target this pathway include inhibiting proteins thought to stabilize N-myc, such as Aurora A kinase (AURKA). While inhibition of AURKA was found to be effective in preclinical tumor studies, no AURKA inhibitors have been approved for clinical use due to a lack of efficacy. Here, we aim to develop chimeric degrader molecules suitable for preclinical and clinical use that degrade AURKA and concomitantly reduce N-myc levels. We used automated solid-phase synthesis to generate a library of >1000 chimeric degraders using derivatives of six known AURKA ligands (Series 1-6). Due to the limitations of using N-myc-driven MB cells in vitro, we employed NB cells as the proof-of-concept model. While the degraders based on five of the ligands showed efficient AURKA degradation, only degraders based on series 3 and 6 could also diminish N-myc. Selected series were further characterized in pharmacokinetic and pharmacodynamic experiments using NB tumor xenografts implanted in the flank in CD1-nude mice. In summary, chimeric degraders based on two individual AURKA ligands efficiently degraded AURKA and N-myc in vitro and in vivo, providing the foundation for further development of novel therapies for patients with N-myc-driven cancers. Further studies will focus on assessing antitumor properties of lead candidates in NB and patient-derived orthotopic MB xenograft models.
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Hu, Chenlin, Yanxia Zuo, Liang Peng, Nanqin Gan, and Lirong Song. "Widespread Distribution and Adaptive Degradation of Microcystin Degrader (mlr-Genotype) in Lake Taihu, China." Toxins 13, no. 12 (December 3, 2021): 864. http://dx.doi.org/10.3390/toxins13120864.
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Microbial degradation is an important route for removing environmental microcystins (MCs). Here, we investigated the ecological distribution of microcystin degraders (mlr-genotype), and the relationship between the substrate specificity of the microcystin degrader and the profile of microcystin congener production in the habitat. We showed that microcystin degraders were widely distributed and closely associated with Microcystis abundance in Lake Taihu, China. We characterized an indigenous degrader, Sphingopyxis N5 in the northern Lake Taihu, and it metabolized six microcystin congeners in increasing order (RR > LR > YR > LA > LF and LW). Such a substrate-specificity pattern was congruent to the order of the dominance levels of these congeners in northern Lake Taihu. Furthermore, a meta-analysis on global microcystin degraders revealed that the substrate-specificity patterns varied geographically, but generally matched the profiles of microcystin congener production in the degrader habitats, and the indigenous degrader typically metabolized well the dominant MC congeners, but not the rare congeners in the habitat. This highlighted the phenotypic congruence between microcystin production and degradation in natural environments. We theorize that such congruence resulted from the metabolic adaptation of the indigenous degrader to the local microcystin congeners. Under the nutrient microcystin selection, the degraders might have evolved to better exploit the locally dominant congeners. This study provided the novel insight into the ecological distribution and adaptive degradation of microcystin degraders.
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Abbineni, Chandrasekhar, Kiran Aithal, Leena Khare, Sandeep Dukare V, Bilash Kuila, Megha Goyal, Khaji Abdul Rawoof, et al. "Abstract A046: Identification of paralog selective degraders of SMARCA2 and SMARCA4 for treatment of various cancers." Molecular Cancer Therapeutics 22, no. 12_Supplement (December 1, 2023): A046. http://dx.doi.org/10.1158/1535-7163.targ-23-a046.
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Abstract Background: The BAF (SWI/SNF) chromatin remodeling complex comprises of two mutually exclusive ATPases, SMARCA2 (BRM) and SMARCA4 (BRG1), that affect the mobilization and positioning of nucleosomes on DNA and thereby regulate important cellular functions including transcription, DNA recombination, DNA repair and chromosome decatenation during mitosis. SMARCA4 is frequently overexpressed in several types of cancers. Overexpression has been linked to increased proliferation and survival, as well as aggressive tumors and poor prognosis. SMARCA4 knockdown in these tumors led to inhibition of proliferation and increased sensitivity to known chemotherapeutic agents, supporting the validity of targeting SMARCA4. Further, genetic silencing studies have established that the oncogenic activity of tumors lacking SMARCA4 is primarily driven by its paralog SMARCA2 containing residual SWI/SNF complex, suggesting the importance of targeting SMARCA2. Considering this well-established biological rationale, selective inhibition/degradation of either of these proteins should be very useful in precision oncology to achieve immense therapeutic benefit. Here we report selective degraders targeting either SMARCA4 or SMARCA2 that demonstrate distinct cellular phenotype. Methods and Results: As part of the initial design plan, selective SMARCA2/4 Bromodomain inhibitors and specific ligands of several E3 ligases were chosen to arrive at different degrader designs. A choice of linkers and different exit vectors were considered to construct a variety of heterobifunctional as well as monovalent degrader molecules. Our proprietary ternary complex modeling algorithm, ALMOND (ALgorithm for MOdeling Neosubstrate Degraders) helped in prioritizing the designs. Shortlisted compounds were synthesized and profiled in multiple cellular assays to understand their degradation potential. Several compounds that potently degrade either SMARCA2 or SMARCA4 selectively were identified. These compounds have shown distinct phenotype depending on the lineage as well as SMARCA2 and SMARCA4 status of the cell lines. As expected, SMARCA2 selective degraders showed exquisite sensitivity to SMARCA4 mutant cell lines (SK-MEL-5 & RERF-LC-A1 etc), whereas SMARCA4 selective degraders showed a distinct cellular sensitivity profile. Potent and selective compounds are being optimized further for their pharmacokinetic properties. Conclusions: Highly potent and selective degraders of either SMARCA2 or SMARCA4 were identified. While selective SMARCA2 degraders have been reported in the literature, to the best of our knowledge, no SMARCA4 selective degrader has been reported so far. Distinct cellular selectivity of these paralog selective degraders supports their further optimization towards advancing them to clinical trials. Citation Format: Chandrasekhar Abbineni, Kiran Aithal, Leena Khare, Sandeep Dukare V, Bilash Kuila, Megha Goyal, Khaji Abdul Rawoof, Dhaytadak Bhagwan Mahadeo, Bhagya M S Kumar, Premkumar M, Swetangini Sahu, Suraj T Gore, Lavanya Krishna N, Charamanna KB, Gopinath CH, Samiulla D S, Subhendu Mukherjee, Thomas Antony, Sanjeev Giri, Shekar Chelur, Kavitha Nellore, Girish Daginakatte, Murali Ramachandra, Susanta Samajdar. Identification of paralog selective degraders of SMARCA2 and SMARCA4 for treatment of various cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A046.
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Uitdehaag, Joost C., Jos e Man, Michelle Muller, Freek an Cauter, Sander an Gemert, Milan Hoffmann, Yvonne G. an Mil, et al. "Abstract 5814: EPriL macrocycles as a platform for the rapid generation of effective kinase degrader antibody conjugates (DACs)." Cancer Research 84, no. 6_Supplement (March 22, 2024): 5814. http://dx.doi.org/10.1158/1538-7445.am2024-5814.
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Abstract The therapeutic success of antibody drug conjugates (ADCs) drives a continuous search for novel payloads that can increase therapeutic window and thereby widen the applications for ADCs. Recently, heterobifunctional degraders have gained great interest as payloads, and degrader antibody conjugates (DACs) are seen as a novel therapeutic modality. Heterobifunctional degraders consist of a small molecule ligand that binds a target (protein of interest or POI), a spacer and an E3 ligase ligand, which can catalyze target degradation. Owing to their catalytic activity, degraders can have better potency than the equivalent inhibitors, making them suitable as ADC payload [1]. Degrader payloads can target a wider variety of mechanisms than classic payloads, which use the same antitumor strategies as chemotherapy, such as tubulin binding or topoisomerase inhibition. Since many FDA-approved targeted therapies are based on the inhibition of protein kinases, we investigated degraders of these kinases as DAC payloads. Kinase DACs could bring enhanced targeting and therefore better therapeutic window to a field where classic ADC payloads have often shown substantial toxicities. As many heterobifunctional degraders show poor cell membrane penetration, their inhibitory potential could be increased as part of a DAC, where endocytic uptake is followed by intracellular release of the degrader payload. To identify kinase degrader payloads, we present a workflow based on a platform called Energetically Privileged Ligands (EPriLs). EPriLs are macrocycle scaffolds that bind non-covalently in the kinase ATP pocket. Their unique binding mode avoids contacts with amino acid positions where resistance to kinase inhibitors frequently occurs. EPriL macrocycles can be decorated appropriately to rationally design specific inhibitors for many therapeutically relevant kinases, and provide synthetic handles to couple them to VHL or CRBN ligands to generate effective kinase degraders. Here we describe how EPriL kinase degraders can be developed into effective DACs, using consecutive libraries of EPriL ligands, spacers, E3 ligase ligands and linkers. First, suitable degraders are identified, based on rapid and deep target degradation and potent antiproliferative activity on target cell lines. Degraders are then transformed into maleimide-linked degraders using convenient attachment of enzymatically cleavable linkers. In a medium throughput fashion, these maleimides are coupled to antibodies to generate DACs, which are tested for stability and biological potency. Applying this workflow to various well-validated kinase targets in oncology resulted in a promising kinase targeting DAC with favorable ADME properties, clear potentiation compared to the parent degrader, and increased selectivity for tumor cell lines. 1] Dragovich et al., Chem. Soc. Rev. (2022) 51, 3886-3897. Citation Format: Joost C. Uitdehaag, Jos e Man, Michelle Muller, Freek an Cauter, Sander an Gemert, Milan Hoffmann, Yvonne G. an Mil, Winfried R. Mulder, Martine B. Prinsen, Jan Gerard Sterrenburg, Diep Vu, Joeri e Wit, Erik Ensing, Rogier C. Buijsman. EPriL macrocycles as a platform for the rapid generation of effective kinase degrader antibody conjugates (DACs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5814.
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Gao, Yang, Baishan Jiang, Hellen Kim, Jianwei Che, Katherine Donovan, John Hatcher, Fidel Huerta, et al. "Abstract 3426: Catalytic degraders effectively address kinase site mutations in EML-ALK oncogenic fusions." Cancer Research 83, no. 7_Supplement (April 4, 2023): 3426. http://dx.doi.org/10.1158/1538-7445.am2023-3426.
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Abstract Heterobifunctional degraders, known as proteolysis targeting chimeras (PROTACs), is an emerging modality for drug discovery, and theoretically possess catalytic mode-of-action, yet few studies have either confirmed or exploited this potential advantage of event-driven pharmacology. Degraders of oncogenic EML4-ALK fusions were developed by conjugating ALK inhibitors to cereblon ligands guided by computational models. To study the sub-stoichiometric capacity of the degrader molecules, simultaneous optimization of pharmacology and compound properties using ternary complex modeling and physicochemical considerations yielded multiple catalytic degraders that were more resilient to clinically relevant ATP-binding site mutations than parental kinase inhibitor drugs. Using HiBiT assay to assess the target degradation and NanoBRET for target occupancy, we illustrated the concept of catalytic degradation of EML4-ALK. Our strategy culminated in the design of the orally bioavailable derivative CPD-1224 that avoided hemolysis (a feature of detergent-like PROTACs), degraded the otherwise recalcitrant compounded mutant L1196M/G1202R in vivo, and commensurately slowed tumor growth, while the third generation ALK inhibitor drug lorlatinib had no effect. These results validate our original therapeutic hypothesis by exemplifying opportunities for catalytic degraders to proactively address binding site resistant mutations in cancer. Citation Format: Yang Gao, Baishan Jiang, Hellen Kim, Jianwei Che, Katherine Donovan, John Hatcher, Fidel Huerta, Nicholas Kwiatkowski, Yingpeng Liu, Peter Liuni, Rebecca J. Metivier, Vineeth Murali, Radosław Nowak, Tinghu Zhang, Eric Fischer, Nathanael Gray, Lyn Jones. Catalytic degraders effectively address kinase site mutations in EML-ALK oncogenic fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3426.
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Bouvier, Corentin, Rachel Lawrence, Francesca Cavallo, Wendy Xolalpa, Allan Jordan, Roland Hjerpe, and Manuel S. Rodriguez. "Breaking Bad Proteins—Discovery Approaches and the Road to Clinic for Degraders." Cells 13, no. 7 (March 26, 2024): 578. http://dx.doi.org/10.3390/cells13070578.
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Proteolysis-targeting chimeras (PROTACs) describe compounds that bind to and induce degradation of a target by simultaneously binding to a ubiquitin ligase. More generally referred to as bifunctional degraders, PROTACs have led the way in the field of targeted protein degradation (TPD), with several compounds currently undergoing clinical testing. Alongside bifunctional degraders, single-moiety compounds, or molecular glue degraders (MGDs), are increasingly being considered as a viable approach for development of therapeutics, driven by advances in rational discovery approaches. This review focuses on drug discovery with respect to bifunctional and molecular glue degraders within the ubiquitin proteasome system, including analysis of mechanistic concepts and discovery approaches, with an overview of current clinical and pre-clinical degrader status in oncology, neurodegenerative and inflammatory disease.
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Baig, Mohammad Hassan, Juhan Bok, Dongmin Kim, Sagar Dattatraya Nale, Yun Sung Jo, Changjoong Kim, Taehhwan Park, Jaejune Dong, and Byoung Gon Moon. "Abstract 4502: Design, synthesis, and evaluation of next-generation EGFR degraders to overcome osimertinib-resistance." Cancer Research 84, no. 6_Supplement (March 22, 2024): 4502. http://dx.doi.org/10.1158/1538-7445.am2024-4502.
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Abstract The occurrence of C797S mutation in epidermal growth factor receptor (EGFR) is a leading mechanism of clinically acquired resistance to third-generation EGFR inhibitors, including Osimertinib. L858R/T790M/C797S and del19/T790M/C797S are commonly observed tertiary EGFR mutants identified in Osimertinib-resistant tumors. As of now, no clinically approved treatment exists that specifically targets these mutants. Here, we report the design and synthesis of a series of highly effective next-generation EGFR degraders effectively degrading EGFR C797S-containing triple mutants. Most compounds demonstrated antiproliferation activity in the subnanomolar range when tested on Ba/F3L858R/T790M/C797S and del19/T790M/C797S cells. Not only C797S but our designed degraders also degraded a wide range of EGFR mutants, including Exon19Del and L858R/T790M (DC50 <100nM). One representative Compound, HDBNJ2812, strongly degrades L858R/T790M/C797S and del19/T790M/C797S with DC50 of 34 nM (Dmax 88.5%) and 14 nM (Dmax 99.7%), respectively. This compound potently inhibits the proliferation of Ba/F3L858R/T790M/C797S (GI50 64 nM) and del19/T790M/C797S (GI50 40 nM). HDBNJ2812 demonstrated high inhibitory potential on HCC827 (del19) and H1975 (L858R/T790M) cell lines (GI50 18.9 and 85 nM, respectively). Furthermore, this degrader demonstrates weak cytotoxicity on non-mutant EGFR-expressing cells, such as A431, WI-26 (human lung fibroblast cells), and CHO-K1 (Chinese hamster ovary cells). Additionally, the in vivo PK/PD findings complement this compound's potential to be considered further. HDBNJ2812 may serve as a lead compound to render the greater therapeutic window for treating resistant non-small cell lung cancer patients with EGFR C797S mutants. Citation Format: Mohammad Hassan Baig, Juhan Bok, Dongmin Kim, Sagar Dattatraya Nale, Yun Sung Jo, Changjoong Kim, Taehhwan Park, Jaejune Dong, Byoung Gon Moon. Design, synthesis, and evaluation of next-generation EGFR degraders to overcome osimertinib-resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4502.
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Vrchotová, Blanka, Petra Lovecká, Milena Dražková, Martina Macková, and Tomas Macek. "Influence of Root Exudates on the Bacterial Degradation of Chlorobenzoic Acids." Scientific World Journal 2013 (2013): 1–8. http://dx.doi.org/10.1155/2013/872026.
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Degradation of chlorobenzoic acids (e.g., products of microbial degradation of PCB) by strains of microorganisms isolated from PCB contaminated soils was assessed. From seven bulk-soil isolates two strains unique in ability to degrade a wider range of chlorobenzoic acids than others were selected, individually and even in a complex mixture of 11 different chlorobenzoic acids. Such a feature is lacking in most tested degraders. To investigate the influence of vegetation on chlorobenzoic acids degraders, root exudates of two plant species known for supporting PCB degradation in soil were tested. While with individual chlorobenzoic acids the presence of plant exudates leads to a decrease of degradation yield, in case of a mixture of chlorobenzoic acids either a change in bacterial degradation specificity, associated with 3- and 4-chlorobenzoic acid, or an extension of the spectrum of degraded chlorobenzoic acids was observed.
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Majeski, Hannah, Akinori Okano, Angela Pasis, Casey Carlson, Qiao Liu, Arvind Shakya, Shenlin Huang, Aparajita Hoskote Chourasia, and Leah Fung. "Abstract 1553: Discovery of CDK4/6 bifunctional degraders for ER+/HER2- breast cancer andtriple negative breast cancer." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1553. http://dx.doi.org/10.1158/1538-7445.am2023-1553.
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Abstract CDK4/6 inhibitors (CDK4/6i) such as palbociclib and ribociclib are used to treatER+/HER2- breast cancer, but patients can develop resistance via mechanismsincluding the INK4-CDK6 complex which have been shown to limit the effectiveness ofCDK4/6i in ER+ breast cancer. Up to 20% patients exhibit innate resistance and up to70% patients develop acquired resistance after 3 years on therapy (Scheidemann,2021). To address this limitation, we utilized our PRODEGY platform of Cereblon(CRBN) binders to synthesize CRBN mediated CDK4/6 bifunctional degraders topotently inhibit tumor growth in CDK4/6i resistant tumors and in treatment naïveER+/HER2- breast cancer and triple negative breast cancer (TNBC). We examined theeffect of our degraders on multiple nodes of this pathway. Target degradation byimmunoblot analysis of TNBC cell line, MDA-MB-231, treated with our CDK4/6bifunctional degraders for 6 hours showed over 50% degradation of CDK4 and CDK6at 10-100nM. Active CDK4/6 phosphorylates the protein RB which releases thetranscription factor E2F, inducing the expression of genes which promote cell cycleprogression. Analysis of RB phosphorylation by in-cell western upon 24 hour ofCDK4/6 degrader treatment showed phospho-RB IC50s at <50nM. Cell cycle analysisby staining with propidium iodide after 24 hours of treatment with CDK4/6 degradersinduced G0/G1 cell cycle arrest at concentrations as low as 10nM. As a readout forgrowth inhibition through cell cycle arrest, we examined the ability of these degradersto inhibit the proliferation of MDA-MB-231 cells in a 2D colony formation assay (CFA)over a 10-day period. Our CDK4/6 degraders showed potent inhibition of cellproliferation with CFA IC50s of <50nM. We demonstrated that our CDK4/6 bifunctionaldegraders were significantly more potent in vitro than the CDK4/6i, palbociclib andribociclib, and the increased activity was due to CRBN mediated target degradation.Our CDK4/6 bifunctional degraders display excellent pharmacokinetic properties inmice with half-lives between 2-10 hours, oral bioavailability between 50-96% and arecurrently being evaluated for tumor growth inhibition against standard of caremolecules in MDA-MB-231 and MCF7 xenograft models. Clinical CDK4/6i are beingevaluated as combinations in TNBC, but the enhanced potency of CDK4/6 degradersin the TNBC cell lines shows that this approach is more promising for this aggressivetype of breast cancer. Reference: Scheidemann, Erin R, and Ayesha N Shajahan-Haq. “Resistance toCDK4/6 Inhibitors in Estrogen Receptor-Positive Breast Cancer.” International journalof molecular sciences vol. 22,22 12292. 14 Nov. 2021, doi:10.3390/ijms222212292 Citation Format: Hannah Majeski, Akinori Okano, Angela Pasis, Casey Carlson, Qiao Liu, Arvind Shakya, Shenlin Huang, Aparajita Hoskote Chourasia, Leah Fung. Discovery of CDK4/6 bifunctional degraders for ER+/HER2- breast cancer andtriple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1553.
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Furukawa, Kastuya, Kazuyuki Shimada, Masahiro Esaki, Kentaro Tanaka, Keisuke Yamamoto, Kiyotoshi Mori, and Hitoshi Kiyoi. "Development and Efficacy of a Novel Bromodomain and Extraterminal Domain Degrader K-256 in MYC/BCL2-Related Lymphoma." Blood 142, Supplement 1 (November 28, 2023): 5008. http://dx.doi.org/10.1182/blood-2023-179334.
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Background: Although intensive chemotherapy is widely used to treat MYC/BCL2-related lymphoma, the efficacy of this treatment modality remains limited and a novel treatment method targeting MYC and BCL2 is therefore desired. While the addition of the BH3 mimetic, venetoclax, to standard immunochemotherapy has shown efficacy in treating diffuse large B-cell lymphoma (DLBCL) with BCL2 expression, bromodomain and extraterminal domain (BET) inhibitors, which suppress MYC transcription, have shown limited efficacy in treating MYC-driven lymphomas. Recently, BET degraders have been developed that irreversibly degrade BET proteins and durably suppress MYC; these degraders show promising therapeutic potential. Method: To improve the prognosis of MYC/BCL2-related lymphoma, we developed a novel BET degrader, K-256, and explored its efficacy both in vitro and in vivo using preclinical models. First, we evaluated the binding activity of K-256 to 32 bromodomains using BROMOscan. Then, we compared the therapeutic effect of K-256 with existing BET inhibitors, including JQ1, OTX-015, and ABBV-075, as well as BET degraders, including dBET6 and ARB-771 in the MYC/BCL2-related lymphoma cell lines SU-DHL4 and SU-DHL6. The therapeutic effects of BET-targeting drugs combined with venetoclax were also evaluated. Finally, we verified the efficacy of K-256 using five MYC/BCL2-related, patient-derived xenograft (PDX) mouse models. Results: K-256 bound selectively to BRD2, BRD3, BRD4, and BRDT, and the Kd value for BRD4, which is most important for MYC transcription, was the lowest (bromodomain 1, 0.027 nM and bromodomain 2, 0.044 nM). We then confirmed that K-256 degraded BRD4 at lower concentrations compared to dBET6 and ARB-771 in SU-DHL4 and SU-DHL6. The GI 50 of K-256 in SU-DHL4 and SU-DHL6 was 12.8 nM and 7.50 nM, respectively, and K-256 induced cell death at lower concentrations than existing drugs (vs. JQ1, OTX-015, and ABBV-075, p < 0.0001; vs. dBET6 and ARV-771, p < 0.01). Immunoblotting analysis showed that K-256, even at a tenth of the concentration, suppressed MYC expression more effectively than existing BET inhibitors and was comparable to existing BET degraders. Moreover, combining K-256 with venetoclax exhibited synergistic effects, both inhibiting cell proliferation and inducing apoptosis in SU-DHL4 and SU-DHL6 cell lines (combination index (CI) of 0.23 and 0.41 for inhibiting cell proliferation, and 0.43 and 0.64 for inducing apoptosis, respectively). In experiments using five MYC/BCL2 PDX cells, K-256 inhibited cell proliferation (GI 50 ranging from 24 to 213 nM) and induced apoptosis (IC 50 ranging from 24 to 229 nM) at lower concentrations than existing BET inhibitors and degraders. As expected, the combination of K-256 with venetoclax also demonstrated synergistic effects in PDX cells, similar to those observed in cell lines (CI of 0.515 to 0.762 for inhibiting cell proliferation; 0.085 to 0.995 for inducing apoptosis). Finally, we confirmed that K-256 showed a stronger therapeutic effect than OTX-015 and ARV-771 in in vivo PDX models. Conclusions : The novel BET degrader, K-256, bound to BET proteins at lower concentrations than existing BET inhibitors and degraders, strongly suppressing MYC expression, primarily via BRD4 degradation. Additionally, K-256 demonstrated superior therapeutic effects in MYC/BCL2-related PDX models both in vitro and in vivo, suggesting that this novel drug could be a promising therapeutic agent for MYC/BCL2-related lymphoma. Its translation to future clinical applications warrants further consideration.
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Shakya, Arvind, Paul Erdman, Chon Lai, Sherry Baker, Chiara Orlandi, Steven Greene, Aparajita Chaurasia, and Leah Fung. "First-in-class PDE4D bifunctional degraders for inflammatory skin diseases." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 238.17. http://dx.doi.org/10.4049/jimmunol.210.supp.238.17.
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Abstract Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by erythema and pruritis, affecting over 15 million people in the US. Th2/Th17 cytokines play a key role in AD pathogenesis, resulting in an increased inflammatory response, disrupted skin barrier, increased susceptibility to infections and allergen sensitization. Phosphodiesterase 4 (PDE4) is a cyclic 3’,5’-adenosine monophosphate (cAMP)-specific phosphodiesterase and its expression is elevated in AD patients sustaining a highly inflammatory environment. PDE4 inhibition has been shown to effectively suppress proinflammatory cytokines in clinically validated approaches for several chronic inflammatory conditions. The current standard of care therapies including PDE4 inhibitors are linked to broad adverse effects due to their off-target activities. Utilizing our proprietary PRODEGY discovery platform, we have designed potent and selective PDE4D bifunctional degraders. PDE4D degradation dramatically decreases the pro-inflammatory cytokines released by activated T cells in vitro. Additionally, PDE4D is degraded efficiently in mice spleens treated with the lead PDE4D degrader in a dose-dependent manner, with no adverse effects. Importantly, our PDE4D degraders do not induce significant degradation of known neo-substrates, suggesting high specificity. Taken together, we propose the introduction of a more potent, specific, and safe PDE4D degrader as novel therapy for inflammatory skin diseases, such as AD.
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Pratibha Jinesh Shah, Jaya Naresh Israni, and Insiya Zulfeqar Lokhandwala. "Study of petrol degrading bacteria and screening for biosurfactants." World Journal of Biology Pharmacy and Health Sciences 18, no. 2 (April 30, 2024): 073–78. http://dx.doi.org/10.30574/wjbphs.2024.18.1.0166.
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Petroleum-based products when mixed with soil, air and water can lead to environmental pollution which can be dangerous for humans. In the current study, soil samples from the petrol unloading area of a petrol pump were collected and nine isolates of petrol degrading bacteria were isolated from the soil by enrichment technique using Bushnell and Hass media. The isolated bacteria could degrade up to 5% petrol and the best degraders were chosen after evaluating their cell mass when grown in the presence of petrol. The percentage of petrol degraded after different intervals of incubation was compared using a UV-vis double beam spectrometer at 228 nm. It was found that the two bacteria - Pseudomonas aeruginosa and Burkholderia cepacia degraded petrol 94.96% and 94.74%, respectively, by day 15 of incubation. The percentage degradation gradually decreased by day 20. Both bacteria were also screened for the production of biosurfactants through haemolysis. It was found that both the bacteria could produce biosurfactant along with them being a potent petrol degrader.
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Patel, Manish R., Rachel Layman, Joy Nolte Fong, Hui Zhang, Su Kim, and Erika Hamilton. "Abstract PO3-19-07: AC699-001, a first in human Phase 1 trial utilizing a novel estrogen receptor chimeric degrader in patients with advanced or metastatic breast cancer." Cancer Research 84, no. 9_Supplement (May 2, 2024): PO3–19–07—PO3–19–07. http://dx.doi.org/10.1158/1538-7445.sabcs23-po3-19-07.
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Abstract Background Estrogen receptors (ER) are hormone-regulated transcription factors that play a critical role in breast cancer initiation and proliferation. Modulation of estrogen activity with therapeutics such as tamoxifen and aromatase inhibitors have been the mainstay therapeutic strategy for ER-positive breast cancer. Several ER-directed therapies have been developed to antagonize the oncogenic ER function, including Selective ER Degraders (SERDs) such as fulvestrant which is approved to treat patients with advanced or metastatic breast cancer. However, it requires intramuscular injection and has poor solubility, thereby limiting its administered dose and therefore its efficacy. In addition to SERDs, a newly emerging technology, E3 ligase-engaged chimeric degraders, has been used to induce potent and deeper ER degradation. Empowered by Accutar's proprietary Protein-Protein Interaction Targeting Chimeras (PPI-TAC) platform, AC699 was meticulously designed as a chimeric degrader to target and degrade the protein of interest, ERα. By effectively linking an ER ligand to an E3-ligase recruiting ligand, AC699 brings ERα in proximity to an E3 ligase, thereby inducing subsequent ubiquitination and degradation of ERα. Notably, chimeric ER degraders possess the unique advantage of degrading the ER protein without the inherent risk of activating an ER signal. Moreover, these molecules are not degraded alongside the target protein allowing for their efficient recycling within the cell. This direct mechanism enables chimeric ER degraders to achieve potent ER degradation with increased specificity, thereby potentially providing a higher therapeutic index compared to SERDs. This abstract describes a first-in-human Phase 1 trial of AC699, a novel ER degrader. Study Description The AC699-001 Phase 1 dose escalation study will enroll up to 60 patients with locally advanced or metastatic ER-positive, human epidermal growth factor receptor 2-negative, breast cancer. Patients must have progressed on standard treatment including at least two prior endocrine regimens or at least one prior line of therapy if combined with a CDK4/6 inhibitor. Prior chemotherapy is not required but must not exceed three prior cytotoxic regimens. Patients must have at least one measurable lesion or at least one predominantly lytic bone lesion. AC699 is given orally, once daily, with doses ranging from 100 mg to 600 mg in a standard 3+3 dose escalation design. The primary objective is to evaluate the safety and tolerability of AC699 using CTCAE 5.0. Secondary objectives include assessing preliminary anti-tumor activity according to RECIST 1.1 and characterizing the pharmacokinetic profile of single and multiple doses of AC699. Enrollment began in December 2022 with five sites in the United States planned. NCT05654532. Citation Format: Manish R Patel, Rachel Layman, Joy Nolte Fong, Hui Zhang, Su Kim, Erika Hamilton. AC699-001, a first in human Phase 1 trial utilizing a novel estrogen receptor chimeric degrader in patients with advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-19-07.
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Majeski, Hannah, Akinori Okano, Angela Pasis, Casey Carlson, Arvind Shakya, Shenlin Huang, Aparajita Hoskote Chourasia, Leah M. Fung, and Qiao Liu. "Discovery of CDK4/6 bifunctional degraders for ER+/HER2- breast cancer." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): 1083. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.1083.
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1083 Background: CDK4/6 inhibitors (CDK4/6i) such as palbociclib and ribociclib are used to treat ER+/HER2- breast cancer, but patients can develop resistance via many mechanisms, several of which converge on the upregulation of CDK6. This has been shown to limit the effectiveness of CDK4/6i in ER+ breast cancer with up to 20% patients exhibiting innate resistance and up to 70% patients developing acquired resistance after 3 years on therapy (Scheidemann, 2021, doi:10.3390/ijms222212292). Methods: To address this limitation, we utilized our PRODEGY platform of Cereblon (CRBN) binders to synthesize CRBN mediated CDK4/6 bifunctional degraders to potently inhibit tumor growth for treatment of naïve ER+/HER2- breast cancer and CDK4/6i resistant tumors. Results: Target degradation by immunoblot analysis of the triple negative breast cancer (TNBC) cell line, MDA-MB-231, treated with our CDK4/6 bifunctional degraders for 6 hours showed up to 85% degradation of CDK4 and CDK6 with DC50s of 1-100nM. CDK4/6 phosphorylates the protein RB which releases the transcription factor E2F, inducing the expression of genes which promote cell cycle progression. Analysis of RB phosphorylation by in-cell western upon 24 hours of CDK4/6 degrader treatment showed phospho-RB IC50s at <30nM. Cell cycle analysis by staining with propidium iodide after 24 hours of treatment with CDK4/6 degraders induced G0/G1 cell cycle arrest at concentrations as low as 10nM. We used a 2D colony formation assay (CFA) as a readout for inhibition of proliferation by cell cycle arrest. Our CDK4/6 degraders showed potent inhibition of cell proliferation with CFA IC50s of <100nM in TNBC cell lines and <25nM in ER+ cell lines, including MCF7, T47D and ZR751 compared to CDK4/6i which ranged from 200nM to 500nM in MCF7 cells. We demonstrated that our CDK4/6 bifunctional degraders were significantly more potent in vitro than the CDK4/6i ribociclib and palbociclib, and the increased activity was due to CRBN mediated target degradation. Our CDK4/6 bifunctional degraders display excellent pharmacokinetic properties in mice with half-lives between 2-10 hours, oral bioavailability between 50-96%. MCF7 xenograft results with our proof-of-concept CDK4/6 degrader showed dose-dependent tumor growth inhibition and greater potency compared to the clinical CDK4/6i ribociclib. We saw tumor regression with our degrader at higher doses which we did not see at any dose of CDK4/6i. Conclusions: Our CDK4/6 bifunctional degraders display excellent single agent activity in vitro and in vivo particularly in comparison to clinically approved CDK4/6i, indicating that using a degrader approach to targeting this pathway may be more effective than current inhibitor therapies.
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Johnsen, Anders R., Stine Schmidt, Trine K. Hybholt, Sidsel Henriksen, Carsten S. Jacobsen, and Ole Andersen. "Strong Impact on the Polycyclic Aromatic Hydrocarbon (PAH)-Degrading Community of a PAH-Polluted Soil but Marginal Effect on PAH Degradation when Priming with Bioremediated Soil Dominated by Mycobacteria." Applied and Environmental Microbiology 73, no. 5 (January 5, 2007): 1474–80. http://dx.doi.org/10.1128/aem.02236-06.
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ABSTRACT Bioaugmentation of soil polluted with polycyclic aromatic hydrocarbons (PAHs) is often disappointing because of the low survival rate and low activity of the introduced degrader bacteria. We therefore investigated the possibility of priming PAH degradation in soil by adding 2% of bioremediated soil with a high capacity for PAH degradation. The culturable PAH-degrading community of the bioremediated primer soil was dominated by Mycobacterium spp. A microcosm containing pristine soil artificially polluted with PAHs and primed with bioremediated soil showed a fast, 100- to 1,000-fold increase in numbers of culturable phenanthrene-, pyrene-, and fluoranthene degraders and a 160-fold increase in copy numbers of the mycobacterial PAH dioxygenase gene pdo1. A nonpolluted microcosm primed with bioremediated soil showed a high rate of survival of the introduced degrader community during the 112 days of incubation. A nonprimed control microcosm containing pristine soil artificially polluted with PAHs showed only small increases in the numbers of culturable PAH degraders and no pdo1 genes. Initial PAH degradation rates were highest in the primed microcosm, but later, the degradation rates were comparable in primed and nonprimed soil. Thus, the proliferation and persistence of the introduced, soil-adapted degraders had only a marginal effect on PAH degradation. Given the small effect of priming with bioremediated soil and the likely presence of PAH degraders in almost all PAH-contaminated soils, it seems questionable to prime PAH-contaminated soil with bioremediated soil as a means of large-scale soil bioremediation.
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Ki, Dong Hyuk, Joonwoo Nam, Eunjung Kim, Hunmi Choi, Chulwon Kim, Jiyeon Kim, Jimmy Jin, Sang-Uk Kang, and Wooseok Han. "Abstract 417: Identification of next-generation EGFR degraders to treat non-small cell lung cancer (NSCLC) patients." Cancer Research 82, no. 12_Supplement (June 15, 2022): 417. http://dx.doi.org/10.1158/1538-7445.am2022-417.
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Abstract Although EGFR-targeted tyrosine kinase inhibitors (TKIs) developed over a couple of decades have made great progress in the treatment of EGFR-mutant driven NSCLC, patients are at great risk to their lives due to drug resistance caused by constantly emerging EGFR mutations. Targeted protein degraders (TPDs), also known as heterobifunctional protein degraders or PROteolysis TArgeting Chimeras (PROTACs), have drawn great attention as a new modality to overcome drug resistance by achieving selective degradation of disease-causing proteins, like an EGFR mutant protein, which are required for the survival and proliferation of various malignant tumor cells. Therefore, we have developed a series of EGFR mutant degraders using BBT-176, a 4th generation EGFR TKI developed by Bridge BioTherapeutics, and novel EGFR inhibitors as warheads which are expected not only to treat various EGFR mutated NSCLC including C797S but also to delay drug resistant-mechanisms by further mutations in the EGFR TKI target site. We synthesized a set of heterobifunctional degraders applying Cyrus BiFx Degrader (CBD) library platform containing different types of linkers and E3 ligase binders. DC50 (half-maximal degradation concentrations) values of the EGFR degraders were obtained in multiple human EGFR mutant NSCLC cell lines, where C-2051, C-2482, and C-4383 showed excellent EGFR degradation potency (DC50 = 7-25 nM, Dmax at 100 nM = 80-97%) with high selectivity against WT EGFR. Among those compounds, C-4383 was potent in cell viability assays with EGFR mutant HCC827 (Del19) and NCI-H1975 (L858R, T790M) cell lines showing a range of GI50 values from 77 to 81 nM at 72 h of compound exposure. By contrast, the compound was much less potent in A549 cells harboring wild-type EGFR (GI50 value at 72 h of treatment, 4.2 μM). We also performed proteomic analysis of C-4383 in H1975 cells resulting that EGFR was the most degraded protein with no off-target events at 100 nM (Dmax dose). A PK study of C-4383 in rats showed good exposure with moderate CL when administered intravenously (CL = 8.51 mL/min/kg, AUC = 5911 ng•h/mL). In summary, we identified heterobifunctional degraders using a 4th generation EGFR inhibitor, BBT-176, that are active in EGFR mutant NSCLC cells harboring single or C797S-containing multiple mutations. We are currently making our efforts on the improvement of physicochemical properties of EGFR mutant targeted heterobifunctional compounds. Citation Format: Dong Hyuk Ki, Joonwoo Nam, Eunjung Kim, Hunmi Choi, Chulwon Kim, Jiyeon Kim, Jimmy Jin, Sang-Uk Kang, Wooseok Han. Identification of next-generation EGFR degraders to treat non-small cell lung cancer (NSCLC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 417.
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Wang, Lanxiang, Yue Liu, Haoran Ni, Wenlong Zuo, Haimei Shi, Weixin Liao, Hongbin Liu, et al. "Systematic characterization of plant-associated bacteria that can degrade indole-3-acetic acid." PLOS Biology 22, no. 11 (November 26, 2024): e3002921. http://dx.doi.org/10.1371/journal.pbio.3002921.
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Plant-associated microbiota affect pant growth and development by regulating plant hormones homeostasis. Indole-3-acetic acid (IAA), a well-known plant hormone, can be produced by various plant-associated bacteria. However, the prevalence of bacteria with the capacity to degrade IAA in the rhizosphere has not been systematically studied. In this study, we analyzed the IAA degradation capabilities of bacterial isolates from the roots of Arabidopsis and rice. Using genomics analysis and in vitro assays, we found that 21 out of 183 taxonomically diverse bacterial isolates possess the ability to degrade IAA. Through comparative genomics and transcriptomic assays, we identified iac-like or iad-like operon in the genomes of these IAA degraders. Additionally, the putative regulator of the operon was found to be highly conserved among these strains through protein structure similarity analysis. Some of the IAA degraders could utilize IAA as their carbon and energy source. In planta, most of the IAA degrading strains mitigated Arabidopsis and rice seedling root growth inhibition (RGI) triggered by exogenous IAA. Moreover, RGI caused by complex synthetic bacterial community can be alleviated by introducing IAA degraders. Importantly, we observed increased colonization preference of IAA degraders from soil to root according to the frequency of the biomarker genes in metagenome-assembled genomes (MAGs) collected from different habitats, suggesting that there is a close association between IAA degraders and IAA producers. In summary, our findings further the understanding of the functional diversity and potential biological roles of plant-associated bacteria in host plant root morphogenesis.
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Zhang, Yujia, Jessica Bates, Benoit Gourdet, Louise Birch, Philip Addis, Roland Hjerpe, and Allan M. Jordan. "Abstract 3429: Beyond cereblon IMIDs - biophysics-based discovery of novel molecular glue chemotypes." Cancer Research 83, no. 7_Supplement (April 4, 2023): 3429. http://dx.doi.org/10.1158/1538-7445.am2023-3429.
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Abstract Molecular glue degraders are compact, low molecular weight molecules that can efficiently induce specific and potent degradation of a target protein. This class of degraders function by inducing interactions between a target of interest and a ubiquitin-ligase, either by stabilization of weak pre-existing interactions, or by generation of entirely novel interactions. These molecules offer significant opportunity beyond heterobifunctional degraders such as PROTACs, not least in terms of improved molecular properties. However, beyond the IMID molecular glues, typified by thalidomide, pomalidomide and lenalidomide, novel molecular glue chemotypes remain scarce. To address this need, we have developed biophysics-based molecular glue screening platform, exploiting our internal, high quality fragment library and proximity-based screening platforms to rapidly identify promising new molecular glues for further optimization. A potential advantage of utilizing cell-free biophysical systems is the opportunity to select both the target and the desired ligase, opening up for development of degraders that capitalize upon differential expression of ligases in different tissues. As proof of concept, we have applied this platform to find new molecular glues to degrade CK1α. This Ser/Thr kinase has been found to be over-expressed in metastatic colorectal cancer, and this over-expression correlates with poor overall survival. The kinase has also been implicated as an oncogenic driver in tumors such as B-Cell lymphomas and non-Hodgkin lymphomas, suggesting a potential therapeutic application for novel CK1α molecular glues. Utilizing known IMID-derived molecular glues between CK1α and CRBN as benchmark controls, we identified several non-IMID derived chemotypes as tentative stabilizers of the CRBN/CK1α interaction. Further studies on these novel candidate degrader templates are now underway. Citation Format: Yujia Zhang, Jessica Bates, Benoit Gourdet, Louise Birch, Philip Addis, Roland Hjerpe, Allan M. Jordan. Beyond cereblon IMIDs - biophysics-based discovery of novel molecular glue chemotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3429.
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Shirasaki, Ryosuke, Sara Gandolfi, Ricardo De Matos Simoes, Geoffrey Matthews, Dennis Buckley, Olga Dashevsky, Sondra L. Downey-Kopyscinski, et al. "CRISPR-Based Functional Genomics Studies Reveal Distinct and Overlapping Genes Mediating Resistance to Different Classes of Heterobifunctional Degraders of Oncoproteins: Implications for Novel Therapeutics across Diverse Neoplasias." Blood 132, Supplement 1 (November 29, 2018): 1367. http://dx.doi.org/10.1182/blood-2018-99-116232.
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Abstract Heterobifunctional proteolysis-targeting chimeric compounds leverage the activity of E3 ligases (e.g. CRBN and VHL) to induce neopmorphic ubiquitination and proteasomal degradation of target oncoproteins, with potent preclinical activity against diverse neoplasias. Despite intense recent efforts to develop pharmacological "degraders" against many different oncoproteins, the mechanisms regulating tumor cell sensitivity to different classes of these "degraders" remain incompletely understood. To address this question in an unbiased manner, we performed genome-scale CRISPR/Cas9-based gene editing loss-of-function (LOF) studies in MM.1S multiple myeloma (MM) cells treated with CRBN-mediated degraders of BET bromodomain proteins (dBET6) or CDK9 (Thal-SNS-032); or with VHL-mediated degraders of BET bromodomain proteins (ARV-771 or MZ-1). We observed that MM cell resistance to any of these "degraders" does not involve genes with recurrent LOF in MM patients and association with high-risk MM (e.g. for TP53, PTEN, negative regulators of cell cycle, et.c.), suggesting that these degraders may exhibit activity against tumor cells with prognostically adverse genetic features. In tumor cells resistant to the CRBN-mediated degraders dBET6 and Thal-SNS-032, we observed significant enrichment of sgRNAs targeting CRBN itself or (to a lesser extent) other components or regulators of its cullin RING ligase (CRLCUL4A) complex, including members of the COP9 signalosome (COPS7A, COPS7B, COPS2, COPS3, COPS8, GPS1, etc.), DDB1, or the E2 ubiquitin conjugating enzyme UBE2G1. In tumor cells resistant to the VHL-mediated degraders MZ-1 and ARV-771, we observed pronounced enrichment of sgRNAs for CUL2, VHL itself, other members (e.g. RBX1, elongin B/C [TCEB1, TCEB2] of the CUL2 complex with VHL), as well as COP9 signalosome genes (COPS7B, COPS8) and UBE2R2. We also validated, using individual sgRNAs for several of these candidate genes that their CRISPR knockout can decrease tumor cell response to dBET6 and Thal-SNS-032 treatment (e.g. for CRBN, COPS7B, COPS2, or COPS8) or MZ-1 and ARV-771 (e.g. for VHL, COP7B and COPS8). Notably, the sgRNAs against COP9 signalosome genes conferred less pronounced decrease in sensitivity to VHL-, than CRBN-based, degraders, suggesting that COP9 signalosome loss has differential roles in the function of CUL4ACRBN vs. CUL2VHL and potentially other CRL complexes. Tumor cells isolated from our CRISPR knockout screens with confirmed resistance to a given degrader were then treated with other degraders operating through the same or different E3 ligase; and against the same or different oncoprotein: we observed cross-resistance between degraders operating through the same E3 ligase against different oncoproteins, but not for degraders targeting the same protein via different E3 ligase/CRLs: this result is consistent with our observation for substantial gene-level differences (despite pathway-level similarities) for resistance mechanisms for CRBN- vs. VHL-based degraders. In conclusion, our study systematically defined at genome-scale the resistance mechanisms of tumor cells against degraders which leverage the same E3 ligase against different targets; or target the same oncoprotein through different E3 ligases/CRL complexes. We observed that for multiple types of degraders, tumor cell resistance is primarily mediated by prevention of, rather than adaptation to, breakdown of the target oncoprotein. The observed pathway-level similarities and major individual gene-level differences in resistance mechanisms for CRBN- and VHL-mediated degraders likely reflects the different composition and regulation of the respective CRL complexes mediating the action of these classes of degraders Our observations suggest that preventing or delaying resistance to pharmacological degradation of oncoproteins may require concurrent or sequential/alternating use of degraders operating through different E3 ligases and ideally, different CRL complexes; while synthetic lethal strategies to prevent COP9 signalosome LOF may also be contemplated to counteract a common, but quantitatively less pronounced, potential mechanism of resistance for several different classes of degraders. Collectively, our study highlights important new directions in the development of new pharmacological degraders for blood cancers and other neoplasias. Disclosures Richardson: Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Licht:Celgene: Research Funding. Boise:Abbvie: Consultancy; AstraZeneca: Honoraria. Gray:C4 Therapeutics: Consultancy. Mitsiades:TEVA: Research Funding; Janssen/ Johnson & Johnson: Research Funding; EMD Serono: Research Funding; Takeda: Other: employment of a relative; Abbvie: Research Funding.
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Agarwal, Anjana, Olusola Peace Osinubi, Komali Vykuntam, Norman Fultang, Neha Bhagwat, Diane Heiser, Kris Vaddi, Koichi Ito, and Peggy Scherle. "Abstract 1594: SMARCA2 (BRM) degraders promotes differentiation and inhibit proliferation in AML models." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1594. http://dx.doi.org/10.1158/1538-7445.am2023-1594.
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Abstract Dysregulated cellular differentiation is a major pathological feature of myeloid malignancies such as acute myeloid leukemia (AML). Targeting cellular differentiation programs has emerged as a novel therapeutic approach to treat patients with AML. Advantages of such differentiation therapy may include fewer systemic side-effects as well as opportunities to target leukemic stem cells (LSCs) and a broader range of clonal populations, likely resulting in lower frequencies of resistance and relapse in AML patients. The success of ATRA and decitabine in subsets of AML patients has proven that inducing differentiation can play a critical role in long-term durable responses. More agents targeting epigenetic regulators have been increasingly studied as differentiation inducers, including LSD1, DNMT1, Menin, and BET inhibitors. Recently, targeting SWI/SNF chromatin remodeling complexes has also been shown to regulate key leukemic gene expression signatures and induce AML differentiation. Small molecule inhibitors as well as gene knockdown for ATP-dependent SWI/SNF subunits SMARCA2 (BRM) and SMARCA4 (BRG1) are associated with re-direction of oncogenic transcriptional regulation to drive cellular differentiation and apoptosis in AML models. We have previously described the activity of highly potent, bispecific SMARCA2 degraders that efficiently promote SMARCA2 protein degradation in preclinical models. In the present study, we investigated the effects of our SMARCA2 selective degraders in AML models. Treatment with SMARCA2 degraders significantly inhibits AML cell line proliferation in vitro with IC50 ranging from 10 to 50 nM. In the SMARCA2 degrader treated cells, expression of PU.1 (SPI1), a key transcription factor in myeloid leukemias, was downregulated. In an in vivo OCI-AML3 xenograft model, treatment with a SMARCA2 selective degrader showed moderate tumor growth inhibition accompanied by robust increases in monocytic maturation markers CD11b and CD14. Further analyses of SMARCA2 degrader effects on global transcriptome and AML immunophenotypes as well as combination effects with other therapies are currently in progress. These findings highlight the potential of SMARCA2 degraders to target AML differentiation blocks and to improve the effectiveness of other therapeutic agents such as decitabine and venetoclax in AML patients. Citation Format: Anjana Agarwal, Olusola Peace Osinubi, Komali Vykuntam, Norman Fultang, Neha Bhagwat, Diane Heiser, Kris Vaddi, Koichi Ito, Peggy Scherle. SMARCA2 (BRM) degraders promotes differentiation and inhibit proliferation in AML models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1594.
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Correa-Garcia, Sara, Vincenzo Corelli, Julien Tremblay, Jessica Ann Dozois, Eugenie Mukula, Armand Séguin, and Etienne Yergeau. "Soil fauna-microbial interactions shifts fungal and bacterial communities under a contamination disturbance." PLOS ONE 18, no. 10 (October 25, 2023): e0292227. http://dx.doi.org/10.1371/journal.pone.0292227.
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The aim of this study was to determine whether the soil faunal-microbial interaction complexity (SFMIC) is a significant factor influencing the soil microbial communities and the willow growth in the context of PAH contamination. The SFMIC treatment had eight levels: just the microbial community, or the microbial community with nematodes, springtails, earthworms and all the possible combinations. SFMIC affected the height and biomass of willows after eight weeks or growth. SFMIC affected the structure and the composition of the bacterial, archaeal and fungal communities, with significant effects of SFMIC on the relative abundance of fungal genera such as Sphaerosporella, a known willow symbiont during phytoremediation, and bacterial phyla such as Actinobacteriota, containing many polycyclic aromatic hydrocarbons (PAH) degraders. These SFMIC effects on microbial communities were not clearly reflected in the community structure and abundance of PAH degraders, even though some degraders related to Actinobacteriota and the diversity of Gram-negative degraders were affected by the SFMIC treatments. Over 95% of PAH was degraded in all pots at the end of the experiment. Overall, our results suggest that, under our experimental conditions, SFMIC changes willow phytoremediation outcomes.
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Morrow, Sara, Dennis Dobrovolsky, Eric Wang, Radosław P. Nowak, Katherine Donovan, Tyler Faust, Guang Yang, et al. "Triple Degradation of BTK, IKZF1 and IKZF3 in B-Cell Malignancies." Blood 132, Supplement 1 (November 29, 2018): 263. http://dx.doi.org/10.1182/blood-2018-99-116895.
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Abstract Bruton's Tyrosine Kinase (BTK), a TEC-family non-receptor tyrosine kinase, plays a critical role in B-cell development and function. Targeting of BTK with covalent inhibitors like ibrutinib has become a standard approach for many B-cell malignancies, including chronic lymphocytic leukemia (CLL), Waldenstrom macroglobulinemia, mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL). Yet, many patients demonstrate intrinsic or acquired resistance to covalent BTK inhibition. The prognosis of patients who relapse after ibrutinib treatment for MCL or CLL is dismal, highlighting the urgent need for new approaches that overcome resistance to current BTK inhibitors. We hypothesized that degradation of BTK could be a better alternative to inhibition alone, as it would both: 1) maintain efficacy in cells harboring the ibrutinib-resistant BTK C418S mutation and 2) target non-catalytic functions of BTK. To address this, we turned to a small molecule-mediated protein degradation platform that utilizes an E3 ligase-targeting moiety linked to the ligand of a target of interest, so that the target can be marked for ubiquitination and subsequent proteasomal degradation. We previously showed that BTK is one of the most robustly degraded kinase targets using a nonspecific kinase inhibitor linked to a imide-based core followed by agnostic proteomics. We synthesized highly potent and selective degraders of BTK using imides as a base. To do so, the parent BTK inhibitor CGI1746 was linked to thalidomide using either polyethylene glycol (DD-03-007) linkers or saturated hydrocarbon chain (DD-03-171) linkers. After verifying that these degraders induce dimerization of BTK and CRBN and penetrate cells, we explored the pharmacological effects in vitro. Both DD-03-007 and DD-03-171 reduced BTK levels at concentrations as low as 40 nM within 4h of treatment. Furthermore, cellular BTK levels remained low for 24h after washout, showing that these degraders are capable of sustaining depletion of BTK for an extended period of time (Figure). DD-03-007 and DD-03-171 are both ligase and proteasome-dependent, as shown by co-treatment with bortezomib or MLN-4924 as well as competition experiments with lenalidomide or CGI-1746. Moreover, the degraders exhibited strong synergy with the HCK inhibitor A419259, suggesting that it would be possible to recapitulate ibrutinib's previously reported polypharmacology with an HCK inhibitor. We overexpressed wild-type or C481S BTK in TMD-8 cells and ran an antiproliferation assay, which showed that DD-03-007 overcame ibrutinib resistance associated with BTK C481S mutation. Next, we explored the effects of the degraders in MCL specifically. Proteomic analysis showed that DD-03-171 is a triple-degrader, as it degrades BTK but retains degradation activity on IKZF1 and IKZF3. Finally, we performed In vivo efficacy studies in cell line and patient-derived xenograft (PDX) models of MCL. The latter was obtained from a patient who had progressed on ibrutinib. In both models, DD-03-171 caused a significant reduction in tumor burden at an early timepoint. DD-03-171 also markedly extended survival compared to treatment with ibrutinib or lenalidomide alone (Figure). In conclusion, we developed highly potent and selective BTK degraders with activity in vivo against human MCL that induce the degradation of multiple factors essential for MCL survival. Figure. Figure. Disclosures Treon: Pharmacyclics: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Johnson & Johnson: Consultancy; BMS: Research Funding. Weinstock:Novartis, Dragonfly, Travera, DxTerity, Travera: Consultancy; Novartis: Consultancy, Research Funding; Novartis, Astra Zeneca, Abbvie, Aileron, Surface Oncology, Daiichi Sankyo: Research Funding; Genentech/Roche, Monsanto: Consultancy; Astra Zeneca, JAX, Samumed, Regeneron, Sun Pharma, Prescient: Patents & Royalties; Travera: Equity Ownership. Gray:Syros, Soltego, Petra, C4 Therapeutics: Equity Ownership.
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Brehmer, Victoria, Stina Lundgren, Tomas Friman, Daniele Amadio, Alexey Chernobrovkin, and Daniel Martinez Molina. "Abstract 3098: CETSA for navigating your chemistry and exploring the biology of protein degraders." Cancer Research 84, no. 6_Supplement (March 22, 2024): 3098. http://dx.doi.org/10.1158/1538-7445.am2024-3098.
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Abstract Protein degradation is a non-classical modality with the potential to tackle therapeutically interesting proteins, previously deemed undruggable. In this area, CETSA is a powerful technology for identifying new binders, assessing target engagement, and investigating the mechanism of action of the degraders in the intact cell environment - without the need to modify your compound, the proteins or the cellular environment. CETSA can provide insights into the binding of the degrader to both the E3 ligase and the protein of interest (POI), as well as follow the downstream cellular and molecular effects. Here we will exemplify how CETSA can be applied in various stages of drug discovery to provide biologically relevant data to guide the design and optimization of new degraders. For example, CETSA can provide valuable information of the cell permeability and the in-cell performance of the degrader, which is important for understanding how the degrader enters cells and reaches its target proteins. By combining data from CETSA with data from degradation readout, in our case quantitative proteomics, it is possible to correlate cellular target engagement potencies with degradation efficiency and importantly, also identify any drug:protein binding that does not result in degradation By using the proteome-wide CETSA Explore format, the selectivity of the degrader and the downstream protein consequences of the elimination of the target protein could be studied. Citation Format: Victoria Brehmer, Stina Lundgren, Tomas Friman, Daniele Amadio, Alexey Chernobrovkin, Daniel Martinez Molina. CETSA for navigating your chemistry and exploring the biology of protein degraders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3098.
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DuTeau, Nancy M., Julia D. Rogers, Christian T. Bartholomay, and Kenneth F. Reardon. "Species-Specific Oligonucleotides for Enumeration ofPseudomonas putida F1, Burkholderia sp. Strain JS150, and Bacillus subtilis ATCC 7003 in Biodegradation Experiments." Applied and Environmental Microbiology 64, no. 12 (December 1, 1998): 4994–99. http://dx.doi.org/10.1128/aem.64.12.4994-4999.1998.
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ABSTRACT Species-specific sequences were identified within the V4 variable region of 16S rRNA of two bacterial species capable of aromatic hydrocarbon metabolism, Pseudomonas putida F1 andBurkholderia sp. strain JS150, and a third, Bacillus subtilis ATCC 7003, that can function as a secondary degrader. Fluorescent in situ hybridization (FISH) with species-specific oligonucleotides was used for direct counting of these species throughout a phenol biodegradation experiment in batch culture. Traditional differential plate counting methods could not be used due to the similar metabolism and interactions of the primary degraders and difficulties in selecting secondary degraders in mixed culture. In contrast, the FISH method provided reliable quantitative results without interference from those factors.
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Farley, Francis J. M. "Degraders and ionization cooling." Nuclear Physics B - Proceedings Supplements 149 (December 2005): 289–94. http://dx.doi.org/10.1016/j.nuclphysbps.2005.05.050.
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Hanan, Emily J., Jun Liang, Xiaojing Wang, Robert A. Blake, Nicole Blaquiere, and Steven T. Staben. "Monomeric Targeted Protein Degraders." Journal of Medicinal Chemistry 63, no. 20 (April 30, 2020): 11330–61. http://dx.doi.org/10.1021/acs.jmedchem.0c00093.
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Miyoshi, Yuna, Jo Okada, Tomotaka Urata, Masaki Shintani, and Kazuhide Kimbara. "A Rotational Slurry Bioreactor Accelerates Biodegradation of A-Fuel in Oil-Contaminated Soil Even under Low Temperature Conditions." Microorganisms 8, no. 2 (February 20, 2020): 291. http://dx.doi.org/10.3390/microorganisms8020291.
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An effective bioaugmentation system for oil-contaminated soil under low-temperature conditions was developed with a rotational slurry bioreactor. Mixtures of two Rhodococcus oil-degraders, strain A and C, which are officially permitted to be used in bioaugmentation in Japan, were inoculated and A-fuel oil was added to a final concentration of 2500 and 5000 mg/kg-slurry. Decomposition tests were carried out for the inoculated samples and non-inoculated samples by rotating at 15 °C, the annual average temperature of Japan. The residue of A-fuel oil and the number of bacteria were measured every two days. After 6 days of treatment, more than 95% of the oil was removed in the inoculated samples, which was more than three times faster than a previous degradation experiment without rotation. A semi-continuous treatment was performed by removing 90% of the treated slurry, then adding the same amount of contaminated slurry into the system without additional degraders. Ninety-four percent of A-fuel oil was successfully degraded after 6 days by this repeated treatment. This could drastically reduce the cost of preparing the degraders. Strikingly, semi-continuous treatment showed oil removal in the non-inoculated samples, indicating that the rotational slurry conditions could efficiently promote biodegradation by indigenous degraders. Our rotational slurry bioreactor accelerated the removal of oil contamination without adding further degraders provides an efficient and cost-effective method of removal of A-fuel oil using a semi-continuous system, which can be used in practical applications in areas with a cooler climate.
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Focht, D. D., D. B. Searles, and S. C. Koh. "Genetic exchange in soil between introduced chlorobenzoate degraders and indigenous biphenyl degraders." Applied and environmental microbiology 62, no. 10 (1996): 3910–13. http://dx.doi.org/10.1128/aem.62.10.3910-3913.1996.
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Hjerpe, Roland, Louise Birch, Alex Brien, Lola Cusin, Lorna Duffy, Benoit Gourdet, Rachel Lawrence, et al. "Abstract 3111: The Sygnature CHARMD platform - combinatorial high-throughput assembly and review of molecular degraders." Cancer Research 83, no. 7_Supplement (April 4, 2023): 3111. http://dx.doi.org/10.1158/1538-7445.am2023-3111.
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Abstract Recent interest the ability to degrade oncogenic proteins has grown exponentially, and the advent of Protein-Targeting Chimeras (PROTACs) has allowed many previously undruggable targets to be specifically targeted. However, the successful development of these bioavailable heterobifunctional degraders relies on the identification of a combination of ligase recruiter, linker and exit vector that allow formation of a competent ternary complex and target degradation. To this end, conventional single-compound synthesis is time-consuming and poses challenges for selection of degrader components with predictive SAR and ADME properties of the assembled bifunctional compound. Here, we demonstrate a high-throughput integrated platform for generation and assessment of bifunctional degraders, incorporating combinatorial chemistry using both commercial and bespoke linkers, cell-based activity assays, and assessment of in vitro DMPK properties (lipophilicity, metabolic stability and experimental polar surface area). Alongside this, we have in place computational methods for ternary complex modelling, linker design and PROTAC prioritisation. Altogether, our approach facilitates rapid screening and identification of bifunctional lead compounds for challenging oncology targets with the potential to deliver significant patient benefit. Our platform approach has been exemplified through application to oncology targets of significant current interests and our results in this area will be highlighted. Citation Format: Roland Hjerpe, Louise Birch, Alex Brien, Lola Cusin, Lorna Duffy, Benoit Gourdet, Rachel Lawrence, Philip MacFaul, Hannah Mortlock, Hannah Neal, Christopher Pearce, Erica Pitti, Gonzalo Robles, Edith Rodrigues, Catriona Scott, Rajesh Singh, Stuart Thomson, Yujia Zhang, Allan Jordan. The Sygnature CHARMD platform - combinatorial high-throughput assembly and review of molecular degraders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3111.
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Dillon, Christian. "Abstract 6052: Systematic identification of novel targeted protein degradation mechanisms using SITESEEKER® technology." Cancer Research 84, no. 6_Supplement (March 22, 2024): 6052. http://dx.doi.org/10.1158/1538-7445.am2024-6052.
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Abstract The rise of Targeted Protein Degradation (TPD) is rapidly changing perceptions about therapeutic target druggability and is rewriting many preconceived notions on drug design. However, the majority of monovalent molecular glue and heterobifunctional degraders in clinical and preclinical development rely predominantly on the recruitment of a single E3 ligase, Cereblon. Arising resistance, toxicities and restricted Protein-of-Interest scope may limit clinical potential, highlighting the need to uncover novel TPD mechanisms. To expand the potential of this modality, we have developed SITESEEKER®, a screening technology operating at substantially greater magnitude of complexity than extant target discovery platforms. SITESEEKER® utilizes computationally-derived encoded mini-protein fragments with huge shape diversity to systematically identify novel degrader mechanisms and define functionally-active binding sites on targets. SITSEEKER® allows for the discovery of targets that may be missed through traditional gene editing or knockdown approaches and can additionally provide valuable mechanistic insights that help to inform, unlock and truncate the path from target ID to drug discovery. We describe the identification of a cache of degrader motifs which showcase the breadth of proteome space yet to be explored within TPD. Moreover, we identify peptide motifs capable of driving degradation in a selective manner with potential to be translated into tissue- or cancer-selective degraders. The functional dependencies of prioritized degraders have been mapped to their cognate E3 ligase using combinatorial screening, giving rise to a number of E3 ligases with potential to be hijacked for TPD. PhoreMost is progressing a pipeline of monovalent and heterobifunctional oncology degrader programs arising from its platform. We demonstrate the effective hijacking of selected E3 ligases, identified by SITESEEKER®, through the discovery of high affinity small molecule binders and subsequent discovery of efficient heterobifunctional degraders against selected Proteins-of-Interest. Citation Format: Christian Dillon. Systematic identification of novel targeted protein degradation mechanisms using SITESEEKER® technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6052.
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Li, Yen-Der, Michelle W. Ma, Muhammad Murtaza Hassan, Kedar Puvar, Mingxing Teng, Brittany Sandoval, Ryan Lumpkin, et al. "Abstract 3424: Template-assisted covalent modification of DCAF16 enables BRD4 molecular glue degraders." Cancer Research 83, no. 7_Supplement (April 4, 2023): 3424. http://dx.doi.org/10.1158/1538-7445.am2023-3424.
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Abstract Molecular glue degraders have emerged as a powerful class of small-molecule therapeutics, as demonstrated by the clinical successes of thalidomide analogs in the treatment of hematological malignancies. These small molecules act by recruiting ubiquitin ligases to disease-relevant proteins, resulting in neosubstrate ubiquitination and degradation. To date, only a small number of ubiquitin ligase - neosubstrate interactions have been exploited by molecular glue degraders, limiting the targeting scope of this therapeutic modality. Covalent chemistry, which confers high binding affinity and the ability of targeting shallow binding sites, can expand the addressable protein interfaces for molecular glue degraders. In this study, we identified a new class of BRD4 covalent molecular glue degraders (GNE-0011, TMX-4137, MMH-252, MMH-272) by derivatizing electrophiles on the solvent-facing side of a non-degradative BRD4 inhibitor, JQ1. These degraders recruit the ubiquitin ligase CUL4DCAF16 to BRD4 via a novel, trans-labeling mechanism we term “template-assisted covalent modification.” These covalent small molecules have only weak reactivity to DCAF16 in the absence of BRD4. However, BRD4 binding allows its BD2 domain, in complex with DCAF16, to serve as a structural template to boost the covalent modification of these degraders to DCAF16. This leads to efficient BRD4-degrader-DCAF16 ternary complex formation and subsequent BRD4 degradation. We solved the cryo-electron microscopy structure of the DDB1-DCAF16 ligase complex bound to BRD4(BD2) and MMH-272, demonstrating that DCAF16 and BRD4(BD2) have pre-existing structural complementarity which optimally orients the reactive moiety of MMH-272 for DCAF16 covalent modification. We performed systematic mutagenesis screens of both DCAF16 and BRD4(BD2) to characterize the drug-induced interaction, discovering that Cys58 of DCAF16 is modified by covalent warheads and is critical for the activity of these degraders, and that His437 of BRD4(BD2) and its adjacent residues are important for a stable interaction with DCAF16. Analysis of a chemical series revealed that the covalent reactivity of these small molecules is required for degradation, and that the degree of reactivity can tune the potency and specificity of the degraders. Our work highlights a new class of BRD4 molecular glue degraders that are enabled by the template-assisted covalent modification of DCAF16. The templated reactivity is likely to exist in other covalent small molecules that engage complementary protein interfaces, and this trans-labeling mechanism can be exploited to develop covalent drugs with more precisely controlled reactivity. Moreover, our findings demonstrate that the decoration of solvent-exposed electrophiles to protein-binding small molecules has great potential to enable discovery and optimization of novel molecular glue degraders. Citation Format: Yen-Der Li, Michelle W. Ma, Muhammad Murtaza Hassan, Kedar Puvar, Mingxing Teng, Brittany Sandoval, Ryan Lumpkin, Scott B. Ficarro, Michelle Y. Wang, Shawn Xu, Brian J. Groendyke, Logan H. Sigua, Isidoro Tavares, Charles Zou, Jonathan M. Tsai, Paul M. Park, Hojong Yoon, Radosław P. Nowak, Jarrod A. Marto, Jun Qi, Katherine A. Donovan, Mikołaj Słabicki, Nathanael S. Gray, Eric S. Fischer, Benjamin L. Ebert. Template-assisted covalent modification of DCAF16 enables BRD4 molecular glue degraders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3424.
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Pilloni, Giovanni, Anne Bayer, Bettina Ruth-Anneser, Lucas Fillinger, Marion Engel, Christian Griebler, and Tillmann Lueders. "Dynamics of Hydrology and Anaerobic Hydrocarbon Degrader Communities in A Tar-Oil Contaminated Aquifer." Microorganisms 7, no. 2 (February 9, 2019): 46. http://dx.doi.org/10.3390/microorganisms7020046.
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Aquifers are typically perceived as rather stable habitats, characterized by low biogeochemical and microbial community dynamics. Upon contamination, aquifers shift to a perturbed ecological status, in which specialized populations of contaminant degraders establish and mediate aquifer restoration. However, the ecological controls of such degrader populations, and possible feedbacks between hydraulic and microbial habitat components, remain poorly understood. Here, we provide evidence of such couplings, via 4 years of annual sampling of groundwater and sediments across a high-resolution depth-transect of a hydrocarbon plume. Specialized anaerobic degrader populations are known to be established at the reactive fringes of the plume. Here, we show that fluctuations of the groundwater table were paralleled by pronounced dynamics of biogeochemical processes, pollutant degradation, and plume microbiota. Importantly, a switching in maximal relative abundance between dominant degrader populations within the Desulfobulbaceae and Desulfosporosinus spp. was observed after hydraulic dynamics. Thus, functional redundancy amongst anaerobic hydrocarbon degraders could have been relevant in sustaining biodegradation processes after hydraulic fluctuations. These findings contribute to an improved ecological perspective of contaminant plumes as a dynamic microbial habitat, with implications for both monitoring and remediation strategies in situ.
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Legros, Celine, Paul Ratcliffe, Vanessa Porkolab, Michele Modugno, and Olivier Mirguet. "Abstract 4501: First reported PIM kinase degraders: Design, profiling & optimization." Cancer Research 84, no. 6_Supplement (March 22, 2024): 4501. http://dx.doi.org/10.1158/1538-7445.am2024-4501.
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Abstract The PIM serine/threonine kinases (PIM1/PIM2/PIM3) are downstream effectors of ABL, JAK2 and Flt-3 oncogenes and are required for tumorigenesis. Overexpression has been reported in hematological and solid tumors, myeloma, lymphoma, leukemia and adenocarcinoma. The first generation of PIM inhibitors to make it to the clinic, including SGI-1776, AZD1208 and PIM447, are known to be pan-PIM inhibitors, while the aim of this project was to identify novel & selective PIM3 inhibitors. To this end, several Hit-finding approaches were employed to rapidly generate novel chemical matter, which were then assessed for their activity against PIM3 using a robust ADP-Glo™ assay. In parallel to this Hit-findings activity, we used AZD1208 scaffold as a starting point to generate PIM3 bifunctional protein degraders and designed a specific screening cascade in order to profile such modalities. The PIM degrader library, synthetized using Automated Robotics Lab, was characterized using ADP-Glo assays. It was then screened on our binding and activity kinase platforms, KINOMEscan® and KinaseProfiler™, and then fully profiled including ternary complex formation with biophysics and in vitro Safety Pharmacology Profiling Panels. One example is the AZD1208 derivate degrader, i.e. EC108154-1, which showed nanomolar range affinity for PIM3 and the E3-ligase CRBN-DDB1, and its affinity range was also confirmed with the ternary complex in SPR and MST-TRIC. This comprehensive screening cascade ensures an in-depth characterization and optimization of protein degraders, with the possibility of monitoring the ternary complex formation with biophysics methods. It is a good illustration of how this combination of tests can be instrumental in selecting the best degraders to progress to the next step of drug discovery. Citation Format: Celine Legros, Paul Ratcliffe, Vanessa Porkolab, Michele Modugno, Olivier Mirguet. First reported PIM kinase degraders: Design, profiling & optimization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4501.
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Conejo-Saucedo, Ulises, Alejandro Ledezma-Villanueva, Gabriela Ángeles de Paz, Mario Herrero-Cervera, Concepción Calvo, and Elisabet Aranda. "Evaluation of the Potential of Sewage Sludge Mycobiome to Degrade High Diclofenac and Bisphenol-A Concentrations." Toxics 9, no. 6 (May 23, 2021): 115. http://dx.doi.org/10.3390/toxics9060115.
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One of the most challenging environmental threats of the last two decades is the effects of emerging pollutants (EPs) such as pharmaceutical compounds or industrial additives. Diclofenac and bisphenol A have regularly been found in wastewater treatment plants, and in soils and water bodies because of their extensive usage and their recalcitrant nature. Due to the fact of this adversity, fungal communities play an important role in being able to safely degrade EPs. In this work, we obtained a sewage sludge sample to study both the culturable and non-culturable microorganisms through DNA extraction and massive sequencing using Illumina MiSeq techniques, with the goal of finding degraders adapted to polluted environments. Afterward, degradation experiments on diclofenac and bisphenol A were performed with the best fungal degraders. The analysis of bacterial diversity showed that Dethiosulfovibrionaceae, Comamonadaceae, and Isosphaeraceae were the most abundant families. A predominance of Ascomycota fungi in the culturable and non-culturable population was also detected. Species such as Talaromyces gossypii, Syncephalastrum monosporum, Aspergillus tabacinus, and Talaromyces verruculosus had remarkable degradation rates, up to 80% of diclofenac and bisphenol A was fully degraded. These results highlight the importance of characterizing autochthonous microorganisms and the possibility of selecting native fungal microorganisms to develop tailored biotransformation technologies for EPs.
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Öztürk, Başak, Johannes Werner, Jan P. Meier-Kolthoff, Boyke Bunk, Cathrin Spröer, and Dirk Springael. "Comparative Genomics Suggests Mechanisms of Genetic Adaptation toward the Catabolism of the Phenylurea Herbicide Linuron in Variovorax." Genome Biology and Evolution 12, no. 6 (May 2, 2020): 827–41. http://dx.doi.org/10.1093/gbe/evaa085.
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Abstract Biodegradation of the phenylurea herbicide linuron appears a specialization within a specific clade of the Variovorax genus. The linuron catabolic ability is likely acquired by horizontal gene transfer but the mechanisms involved are not known. The full-genome sequences of six linuron-degrading Variovorax strains isolated from geographically distant locations were analyzed to acquire insight into the mechanisms of genetic adaptation toward linuron metabolism. Whole-genome sequence analysis confirmed the phylogenetic position of the linuron degraders in a separate clade within Variovorax and indicated that they unlikely originate from a common ancestral linuron degrader. The linuron degraders differentiated from Variovorax strains that do not degrade linuron by the presence of multiple plasmids of 20–839 kb, including plasmids of unknown plasmid groups. The linuron catabolic gene clusters showed 1) high conservation and synteny and 2) strain-dependent distribution among the different plasmids. Most of them were bordered by IS1071 elements forming composite transposon structures, often in a multimeric array configuration, appointing IS1071 as a key element in the recruitment of linuron catabolic genes in Variovorax. Most of the strains carried at least one (catabolic) broad host range plasmid that might have been a second instrument for catabolic gene acquisition. We conclude that clade 1 Variovorax strains, despite their different geographical origin, made use of a limited genetic repertoire regarding both catabolic functions and vehicles to acquire linuron biodegradation.
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Sawant, Rajiv, Matthis Geitmann, Thomas Gossas, Wei B. Emond, Ulf Bremberg, Konrad Koehler, Michele Ceribelli, Craig J. Thomas, and Peter Brandt. "Abstract LB029: Degraders of TEAD transcription factors based on interface 3 binders." Cancer Research 84, no. 7_Supplement (April 5, 2024): LB029. http://dx.doi.org/10.1158/1538-7445.am2024-lb029.
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Abstract TEAD transcription factors have emerged as clinically validated targets for Hippo-altered cancers, e.g. mesothelioma driven by NF2 inactivation/deficiency. We have developed a series of novel small molecule targeted protein degraders of TEAD based on pan-TEAD interface 3 ligands. In cells, the compounds induce degradation of TEAD by formation of a ternary complex with Cereblon, leading to ubiquitination of TEAD and subsequent proteasomal degradation. In a cell-based luciferase reporter assay the degraders show low nanomolar activity. The downstream effects of TEAD degradation were further investigated by qPCR and WB analyses of bona fide YAP-TEAD target genes such as CTGF, Cyr61 and AMOTL2. The effectiveness of the TEAD degraders were compared to other classes of TEAD modulators such as palmitoylation inhibitors and YAP-TEAD protein-protein inhibitors by means of cellular viability assays using various mesothelioma cell lines. Finally, we performed an unbiased, quantitative high-throughput drug combination screening by combining a TEAD degrader with a library of approximately 2,800 oncology-focused drugs. This research was supported in part by the Intramural/Extramural research program of the NCATS, NIH. Citation Format: Rajiv Sawant, Matthis Geitmann, Thomas Gossas, Wei B. Emond, Ulf Bremberg, Konrad Koehler, Michele Ceribelli, Craig J. Thomas, Peter Brandt. Degraders of TEAD transcription factors based on interface 3 binders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB029.
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Mainetti, Tamara, Marilena Palmisano, Fabio Rezzonico, Blaž Stres, Susanne Kern, and Theo H. M. Smits. "Broad diversity of bacteria degrading 17ß-estradiol-3-sulfate isolated from river sediment and biofilm at a wastewater treatment plant discharge." Archives of Microbiology 203, no. 7 (June 3, 2021): 4209–19. http://dx.doi.org/10.1007/s00203-021-02409-0.
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AbstractConjugated estrogens, such as 17β-estradiol-3-sulfate (E2-3S), can be released into aquatic environments through wastewater treatment plants (WWTP). There, they are microbiologically degraded into free estrogens, which can have harmful effects on aquatic wildlife. Here, the degradation of E2-3S in environmental samples taken upstream, downstream and at the effluent of a WWTP was assessed. Sediment and biofilm samples were enriched for E2-3S-degrading microorganisms, yielding a broad diversity of bacterial isolates, including known and novel degraders of estrogens. Since E2-3S-degrading bacteria were also isolated in the sample upstream of the WWTP, the WWTP does not influence the ability of the microbial community to degrade E2-3S.
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Begovich, Kyle, Angela Schoolmeesters, Navin Rajapakse, Elena Martinez, Qiao Liu, Arvind Shakya, Akinori Okano, et al. "Abstract 6056: Identification of first-in-class, orally bioavailable SOS1 bifunctional degraders for the treatment of KRAS- and RTK-driven cancers." Cancer Research 84, no. 6_Supplement (March 22, 2024): 6056. http://dx.doi.org/10.1158/1538-7445.am2024-6056.
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Abstract Monotherapies which target nodes within the RTK-RAS-MAPK pathway often display early potency in the clinic, but their preliminary response is limited as tumors begin to regrow due to adaptive and acquired resistance mechanisms. Disrupting proteins that mitigate either type of resistance mechanism in combination with oncogene-targeted agents could help extend and enhance the clinical potential of these drugs. Son of Sevenless 1 (SOS1), a RAS guanine nucleotide exchange factor, is a highly attractable protein to target given its role in transducing inputs from upstream receptor tyrosine kinases (RTKs) to downstream RAS proteins to regulate signaling pathways involved in cell proliferation and survival. Additionally, SOS1 is subject to MAPK-mediated negative feedback inhibition and drugs targeting upstream and downstream nodes relieves SOS1 from this inhibition resulting in pathway reactivation. To address this need, we have developed orally bioavailable SOS1 bifunctional degraders for cancers driven by KRAS and RTKs. Our top two lead molecules demonstrate CRBN- and proteasomal-mediated SOS1 degradation with DC50s < 10nM and maximum degradation > 90%. Consistent with this notion, SOS1 degradation inhibited downstream signaling marker phopshoERK with IC50s < 5nM and were 26- or 53-fold more potent when compared to the clinical SOS1 inhibitor. Notably, the SOS1 degraders exhibited weaker SOS1 binding compared to other SOS1 inhibitors highlighting that the potency is heavily driven by the catalytic nature of degradation rather than occupancy-driven events. Both SOS1 degraders displayed CRBN- and SOS1-dependent antiproliferative activity in KRAS- and EGFR- mutant, solid tumor cell lines as well as in BCR-ABL driven, CML cells with IC50 values ranging from 0.5-10nM. Consistent with our in vitro data, oral administration of our SOS1 degraders in mice harboring H358 (KRAS G12C) and H441 (KRAS G12V) xenografts resulted in SOS1 degradation, phosphoERK reduction and significant tumor growth inhibition. While SOS1 degrader monotherapy demonstrated in vitro and in vivo potency, combination of mutant or allele specific EGFR and KRAS inhibitors and ABL inhibitors with our proof-of-concept degraders prevented pathway reactivation associated with these inhibitors and lead to a more durable response. These combinations also yielded synergistic effects in in vitro proliferation assays as well as enhanced tumor growth inhibition in KRAS-mutant xenograft models. Together, our SOS1 degraders alone and in combination with other targeted agents demonstrated anti-tumor activity in a variety of KRAS- and RTK-driven cancer cell lines and xenograft models. These results support the potential of orally bioavailable SOS1 degraders to help mitigate pathway reactivation for enhanced efficacy and prolonged response duration. Citation Format: Kyle Begovich, Angela Schoolmeesters, Navin Rajapakse, Elena Martinez, Qiao Liu, Arvind Shakya, Akinori Okano, Venkat Mali, Shenlin Huang, Aparajita Chourasia, Leah Fung. Identification of first-in-class, orally bioavailable SOS1 bifunctional degraders for the treatment of KRAS- and RTK-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6056.
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Chang, Yu, Jianzhang Yang, Jean Ching-Yi Tien, Zhen Wang, Yang Zhou, Pujuan Zhang, Weixue Huang, et al. "Abstract 3428: Discovery of a highly potent and selective dual PROTAC degrader of CDK12 and CDK13." Cancer Research 83, no. 7_Supplement (April 4, 2023): 3428. http://dx.doi.org/10.1158/1538-7445.am2023-3428.
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Abstract Selective degradation of the cyclin-dependent kinases 12 and 13 (CDK12/13) presents a novel therapeutic opportunity for triple-negative breast cancer (TNBC), but there is still a lack of dual CDK12/13 degraders. Here, we report the discovery of the first series of highly potent and selective dual CDK12/13 degraders by employing the proteolysis-targeting chimera (PROTAC) technology. The optimal compound 7f effectively degraded CDK12 and CDK13 with DC50 values of 2.2 nM and 2.1 nM, respectively, in MDA-MB-231 breast cancer cells. Global proteomic profiling demonstrated the target selectivity of 7f. In vitro, 7f suppressed expression of core DNA damage response (DDR) genes in a time- and dose-dependent manner. Further, 7f markedly inhibited proliferation of multiple TNBC cell lines including MFM223, with an IC50 value of 47 nM. Importantly, 7f displayed a significantly improved anti-proliferative activity compared to the structurally similar inhibitor 4.The 2nd generation CDK12/13 degrader 9069 was further developed, which showed more potent degradation on both CDK12 and CDK13. Interestingly, multiple prostate cancer cell lines were sensitive to 9069, such as VCaP, 22RV1 and LAPC4 with IC50 values of 22.9, 90.3 and 152.1 nM, respectively. In vivo studies showed a potent tumor growth inhibition in both VCaP CRPC xenograft and PC310 PDX prostate cancer models. These results suggest the potential application of a CDK12/13 degrader for the treatment of TNBC and prostate cancer. Citation Format: Yu Chang, Jianzhang Yang, Jean Ching-Yi Tien, Zhen Wang, Yang Zhou, Pujuan Zhang, Weixue Huang, Josh Vo, Ingrid J. Apel, Cynthia Wang, Victoria Zhixuan Zeng, Yunhui Cheng, Shuqin Li, George Xiaoju Wang, Ke Ding, Arul M. Chinnaiyan. Discovery of a highly potent and selective dual PROTAC degrader of CDK12 and CDK13 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3428.
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Feld, Louise, Tue Kjærgaard Nielsen, Lars Hestbjerg Hansen, Jens Aamand, and Christian Nyrop Albers. "Establishment of Bacterial Herbicide Degraders in a Rapid Sand Filter for Bioremediation of Phenoxypropionate-Polluted Groundwater." Applied and Environmental Microbiology 82, no. 3 (November 20, 2015): 878–87. http://dx.doi.org/10.1128/aem.02600-15.
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ABSTRACTIn this study, we investigated the establishment of natural bacterial degraders in a sand filter treating groundwater contaminated with the phenoxypropionate herbicides (RS)-2-(4-chloro-2-methylphenoxy)propanoic acid (MCPP) and (RS)-2-(2,4-dichlorophenoxy)propanoic acid (DCPP) and the associated impurity/catabolite 4-chlorophenoxypropanoic acid (4-CPP). A pilot facility was set up in a contaminated landfill site. Anaerobic groundwater was pumped up and passed through an aeration basin and subsequently through a rapid sand filter, which is characterized by a short residence time of the water in the filter. For 3 months, the degradation of DCPP, MCPP, and 4-CPP in the sand filter increased to 15 to 30% of the inlet concentration. A significant selection for natural bacterial herbicide degraders also occurred in the sand filter. Using a most-probable-number (MPN) method, we found a steady increase in the number of culturable phenoxypropionate degraders, reaching approximately 5 × 105degraders per g sand by the end of the study. Using a quantitative PCR targeting the two phenoxypropionate degradation genes,rdpAandsdpA, encoding stereospecific dioxygenases, a parallel increase was observed, but with the gene copy numbers being about 2 to 3 log units higher than the MPN. In general, thesdpAgene was more abundant than therdpAgene, and the establishment of a significant population of bacteria harboringsdpAoccurred faster than the establishment of anrdpAgene-carrying population. The identities of the specific herbicide degraders in the sand filter were assessed by Illumina MiSeq sequencing of 16S rRNA genes from sand filter samples and from selected MPN plate wells. We propose a list of potential degrader bacteria involved in herbicide degradation, including representatives belonging to theComamonadaceaeandSphingomonadales.
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Aguilar, Angelo, Jiuling Yang, Yangbing Li, Donna McEachern, and Shaomeng Wang. "Abstract 4515: Orally bioavailable PROTAC based MDM2 degrader." Cancer Research 84, no. 6_Supplement (March 22, 2024): 4515. http://dx.doi.org/10.1158/1538-7445.am2024-4515.
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Abstract Activation of the tumor suppressor p53, through inhibition of the MDM2 protein, has been pursued as a cancer therapeutic strategy and has produced many distinct inhibitors that are in clinical trials. A limitation arising from inhibiting the MDM2-p53 interaction is the upregulation of MDM2, itself a target gene of p53, and this attenuates the activation of p53 and efficacy of the inhibitors. To circumvent this limitation, we previously reported the first PROTAC based MDM2 degraders. These induced and sustained robust degradation of MDM2, achieved stronger p53 activation, and more potent anticancer activity than MDM2 inhibitors thus representing a new therapeutic strategy for targeting MDM2. Currently, all the PROTAC based MDM2 degraders are all dosed intravenously. Here we describe our design, synthesis, and optimizations that led to the discovery of the first orally bioavailable PROTAC based MDM2 degrader and our investigation of its therapeutic potential and mechanism of action. Consistent with its design to effectively degrade MDM2, our PROTAC effectively induces rapid degradation of MDM2 resulting in accumulation of wild-type p53 protein and activates p53 transcriptional activity in leukemia cells without accumulation of MDM2 protein. Consequently, it potently inhibits cell growth and induces apoptosis at low nano-molar concentrations in ALL and AML cell lines >10-100 times more potent than MDM2 inhibitors; and, after 50 mg/kg oral dose, 5 days/week for 3 weeks, it increased the median survival by 26 days of mice with disseminated RS4;11 cancer. Citation Format: Angelo Aguilar, Jiuling Yang, Yangbing Li, Donna McEachern, Shaomeng Wang. Orally bioavailable PROTAC based MDM2 degrader [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4515.
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Nowak, Radoslaw. "Structure-based design of degraders." Acta Crystallographica Section A Foundations and Advances 77, a1 (July 30, 2021): a71. http://dx.doi.org/10.1107/s0108767321099281.
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Brenner, V. "Genetic construction of PCB degraders." International Biodeterioration & Biodegradation 37, no. 3-4 (January 1996): 254. http://dx.doi.org/10.1016/0964-8305(96)88322-3.
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Aydin, Dilan Camille, and Bulent Icgen. "Monorhamnolipids Predominance among Kerosene Degraders." Journal of Environmental Engineering 146, no. 6 (June 2020): 04020036. http://dx.doi.org/10.1061/(asce)ee.1943-7870.0001710.
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Brenner, Vladimir, Joseph J. Arensdorf, and Dennis D. Focht. "Genetic construction of PCB degraders." Biodegradation 5, no. 3-4 (December 1994): 359–77. http://dx.doi.org/10.1007/bf00696470.
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Shi En Kim. "New collaboration on protein degraders." C&EN Global Enterprise 101, no. 25 (July 31, 2023): 13. http://dx.doi.org/10.1021/cen-10125-buscon17.
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Layman, Rachel M., Manish R. Patel, David Cosgrove, Michael Danso, Nancy Mota, Marjorie E. Zettler, Katherine C. Pehlivan, and Erika Hamilton. "Abstract CT075: A Phase 1 trial evaluating AC699, an orally bioavailable chimeric estrogen receptor degrader, in patients with advanced or metastatic breast cancer." Cancer Research 84, no. 7_Supplement (April 5, 2024): CT075. http://dx.doi.org/10.1158/1538-7445.am2024-ct075.
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Abstract Background The role of estrogen receptor (ER) signaling in driving breast carcinogenesis is well established, and endocrine therapy has been a mainstay in the treatment of patients with ER-positive advanced or metastatic breast cancer for decades. Aromatase inhibitors, selective estrogen receptor modulators, and selective ER degraders (SERDs) such as fulvestrant, and more recently elacestrant, are integral components of the therapeutic strategy for patients with ER-positive breast cancer. However, unmet medical need persists in this patient population, due to suboptimal clinical outcomes and the development of resistance to therapy. E3 ligase-engaged chimeric degraders represent a technological advance with the potential to induce potent and deeper ER degradation. Utilizing Accutar's proprietary Protein-Protein Interaction Targeting Chimeras (PPI-TAC) platform, AC699 was designed as a novel chimeric degrader targeting ERα. By effectively linking an ER ligand to an E3-ligase recruiting ligand, AC699 brings ERα in proximity to an E3 ligase, resulting in ubiquitination and subsequent degradation of ERα. Chimeric ER degraders possess the unique advantage of degrading the ER protein without the inherent risk of activating an ER signal. Moreover, these molecules are not degraded alongside the target protein, allowing for their efficient recycling within the cell. This direct mechanism enables chimeric ER degraders to achieve potent ER degradation with increased specificity, thereby potentially providing a higher therapeutic index compared to SERDs. Study Description The AC699-001 trial is a first in human Phase 1 dose escalation study (NCT05654532) which will enroll up to 60 patients with locally advanced or metastatic ER-positive, human epidermal growth factor receptor 2-negative, breast cancer. Patients must have received at least two prior lines of endocrine treatment, or at least one prior line, if combined with a CDK4/6 inhibitor. Prior chemotherapy is not required but must not exceed three prior lines of cytotoxic treatment. Patients must have at least one measurable lesion or at least one predominantly lytic bone lesion. AC699 is administered orally, once daily, with doses ranging from 100 mg to 600 mg in a standard 3+3 dose escalation design. The primary objective is evaluation of the safety and tolerability of AC699. Secondary objectives include assessment of preliminary anti-tumor activity and characterization of the pharmacokinetic profile of single and multiple doses of AC699. Enrollment began in December 2022 and a total of 5 sites have been activated in the United States. Citation Format: Rachel M. Layman, Manish R. Patel, David Cosgrove, Michael Danso, Nancy Mota, Marjorie E. Zettler, Katherine C. Pehlivan, Erika Hamilton. A Phase 1 trial evaluating AC699, an orally bioavailable chimeric estrogen receptor degrader, in patients with advanced or metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT075.
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Dong, Xiaowu, Yu Guo, Jingyu Zhang, Zheyuan Shen, Shuang Wu, Shuangshuang Geng, Xinna Ma, Miao Hu, and Xinglu Zhou. "Potent in Vitro and In Vivo Efficacy of Hdz-C123A, a GSPT1 Degrader-Antibody Conjugate Targeting CD123 in Acute Myeloid Leukemia." Blood 144, Supplement 1 (November 5, 2024): 156. https://doi.org/10.1182/blood-2024-201221.
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Introduction: Antibody-drug conjugates (ADCs), as an emerging class of targeted therapies, have garnered significant attention in cancer treatment due to their clinical potential in recent years. Currently, most ADC payloads are cytotoxic agents, prompting the need for novel payloads. Given the catalytic mechanism of action and expanded targeting capabilities, degraders are considered potential candidates for the next-generation payloads. We identified a potent and conjugable GSPT1 degrader CDG0501 through our Rosetta For Molecule Glue (RFMG) model and CRBN-based degrader library. Considering CD123 is a cell surface protein overexpressed in several hematologic malignancies, including AML and myelodysplastic syndrome (MDS), with restricted expression in normal hematopoietic stem cells, CDG0501 was conjugated to a humanized IgG1 targeting CD123 via a tumor-enriched protease-cleavable linker, resulting in HDZ-C123A, a stable and homogeneous conjugate with a drug-to-antibody ratio of 8. After a series of evaluations, HDZ-C123A has been validated as a promising pre-clinical candidate for further clinical development. Results: CDG0501 showed sub-nanomolar to nanomolar activity against multiple acute myeloid leukemia (AML) and non-Hodgkin lymphoma (NHL) cell lines. In CD123-expressing cell lines, HDZ-C123A exhibited picomolar proliferative inhibition activity, which was 20-1000 times more potent than several GSPT1 degraders, including CC-90009, and showed robust activity in Mylotarg-resistant cell lines. Ex vivo experiments revealed a stronger potency of HDZ-C123A in AML patient-derived blasts compared to CC-90009 and venetoclax. HDZ-C123A demonstrated minimal toxicity to peripheral blood mononuclear cells derived from healthy subjects, highlighting the potential of conjugation strategies to improve degraders' narrow therapeutic index. HDZ-C123A showed significant anti-tumor efficacy and safety in several hematologic xenograft models and patient-derived models following single-dose administration. Particularly in the MV4-11 xenograft model, complete response was observed at doses as low as 1 mg/kg, Pharmacodynamic studies demonstrated that tumor growth inhibition correlated with the abundance of GSPT1 and related biomarkers. Conclusions: In summary, CDG0501, as a potent GSPT1 degrader, demonstrates potential as a next-generation payload in preclinical studies. HDZ-C123A, constructed based on CDG0501, shows promising potential as a first-in-class CD123-targeting degrader-antibody conjugate for AML treatment.