Relevant bibliographies by topics / Ligase I Inhibitors

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Academic literature on the topic 'Ligase I Inhibitors'

Author: Grafiati
Published: 6 September 2023

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Journal articles on the topic "Ligase I Inhibitors"

1

Alomari, Arqam, Robert Gowland, Callum Southwood, Jak Barrow, Zoe Bentley, Jashel Calvin-Nelson, Alice Kaminski, et al. "Identification of Novel Inhibitors of Escherichia coli DNA Ligase (LigA)." Molecules 26, no. 9 (April 25, 2021): 2508. http://dx.doi.org/10.3390/molecules26092508.

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Present in all organisms, DNA ligases catalyse the formation of a phosphodiester bond between a 3′ hydroxyl and a 5′ phosphate, a reaction that is essential for maintaining genome integrity during replication and repair. Eubacterial DNA ligases use NAD+ as a cofactor and possess low sequence and structural homology relative to eukaryotic DNA ligases which use ATP as a cofactor. These key differences enable specific targeting of bacterial DNA ligases as an antibacterial strategy. In this study, four small molecule accessible sites within functionally important regions of Escherichia coli ligase (EC-LigA) were identified using in silico methods. Molecular docking was then used to screen for small molecules predicted to bind to these sites. Eight candidate inhibitors were then screened for inhibitory activity in an in vitro ligase assay. Five of these (geneticin, chlorhexidine, glutathione (reduced), imidazolidinyl urea and 2-(aminomethyl)imidazole) showed dose-dependent inhibition of EC-LigA with half maximal inhibitory concentrations (IC50) in the micromolar to millimolar range (11–2600 µM). Two (geneticin and chlorhexidine) were predicted to bind to a region of EC-LigA that has not been directly investigated previously, raising the possibility that there may be amino acids within this region that are important for EC-LigA activity or that the function of essential residues proximal to this region are impacted by inhibitor interactions with this region. We anticipate that the identified small molecule binding sites and inhibitors could be pursued as part of an antibacterial strategy targeting bacterial DNA ligases.
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Ciarrocchi, Giovanni, Donald G. MacPhee, Les W. Deady, and Leann Tilley. "Specific Inhibition of the Eubacterial DNA Ligase by Arylamino Compounds." Antimicrobial Agents and Chemotherapy 43, no. 11 (November 1, 1999): 2766–72. http://dx.doi.org/10.1128/aac.43.11.2766.

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ABSTRACT All known DNA ligases catalyze the formation of a phosphodiester linkage between adjacent termini in double-stranded DNA via very similar mechanisms. The ligase family can, however, be divided into two classes: eubacterial ligases, which require NAD+ as a cofactor, and other ligases, from viruses, archaea, and eukaryotes, which use ATP. Drugs that discriminate between DNA ligases from different sources may have antieubacterial activity. We now report that a group of arylamino compounds, including some commonly used antimalarial and anti-inflammatory drugs and a novel series of bisquinoline compounds, are specific inhibitors of eubacterial DNA ligases. Members of this group of inhibitors have different heterocyclic ring systems with a common amino side chain in which the two nitrogens are separated by four carbon atoms. The potency, but not the specificity of action, is influenced by the DNA-binding characteristics of the inhibitor, and the inhibition is noncompetitive with respect to NAD+. The arylamino compounds appear to target eubacterial DNA ligase in vivo, since a SalmonellaLig− strain that has been rescued with the ATP-dependent T4 DNA ligase is less sensitive than the parentalSalmonella strain.
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Lama, Rati, Samuel L. Galster, Chao Xu, Luke W. Davison, Sherry R. Chemler, and Xinjiang Wang. "Dual Targeting of MDM4 and FTH1 by MMRi71 for Induced Protein Degradation and p53-Independent Apoptosis in Leukemia Cells." Molecules 27, no. 22 (November 8, 2022): 7665. http://dx.doi.org/10.3390/molecules27227665.

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MDM2 and MDM4 are cancer drug targets validated in multiple models for p53-based cancer therapies. The RING domains of MDM2 and non-p53-binder MDM2 splice isoforms form RING domain heterodimer polyubiquitin E3 ligases with MDM4, which regulate p53 stability in vivo and promote tumorigenesis independent of p53. Despite the importance of the MDM2 RING domain in p53 regulation and cancer development, small molecule inhibitors targeting the E3 ligase activity of MDM2-MDM4 are poorly explored. Here, we describe the synthesis and characterization of quinolinol derivatives for the identification of analogs that are capable of targeting the MDM2-MDM4 heterodimer E3 ligase and inducing apoptosis in cells. The structure-activity-relationship (SAR) study identified structural moieties critical for the inhibitory effects toward MDM2-MDM4 E3 ligase, the targeted degradation of MDM4 and FTH1 in cells, and anti-proliferation activity. Lead optimization led to the development of compound MMRi71 with improved activity. In addition to accumulating p53 proteins in wt-p53 bearing cancer cells as expected of any MDM2 inhibitors, MMRi71 effectively kills p53-null leukemia cells, an activity that conventional MDM2-p53 disrupting inhibitors lack. This study provides a prototype structure for developing MDM4/FTH1 dual-targeting inhibitors as potential cancer therapeutics.
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Shapiro, Adam B., Ann E. Eakin, Grant K. Walkup, and Olga Rivin. "A High-Throughput Fluorescence Resonance Energy Transfer-Based Assay for DNA Ligase." Journal of Biomolecular Screening 16, no. 5 (March 11, 2011): 486–93. http://dx.doi.org/10.1177/1087057111398295.

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DNA ligase is the enzyme that catalyzes the formation of the backbone phosphodiester bond between the 5′-PO4 and 3′-OH of adjacent DNA nucleotides at single-stranded nicks. These nicks occur between Okazaki fragments during replication of the lagging strand of the DNA as well as during DNA repair and recombination. As essential enzymes for DNA replication, the NAD+-dependent DNA ligases of pathogenic bacteria are potential targets for the development of antibacterial drugs. For the purposes of drug discovery, a high-throughput assay for DNA ligase activity is invaluable. This article describes a straightforward, fluorescence resonance energy transfer–based DNA ligase assay that is well suited for high-throughput screening for DNA ligase inhibitors as well as for use in enzyme kinetics studies. Its use is demonstrated for measurement of the steady-state kinetic constants of Haemophilus influenzae NAD+-dependent DNA ligase and for measurement of the potency of an inhibitor of this enzyme.
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Gorelik, Maryna, Stephen Orlicky, Maria A. Sartori, Xiaojing Tang, Edyta Marcon, Igor Kurinov, Jack F. Greenblatt, et al. "Inhibition of SCF ubiquitin ligases by engineered ubiquitin variants that target the Cul1 binding site on the Skp1–F-box interface." Proceedings of the National Academy of Sciences 113, no. 13 (March 14, 2016): 3527–32. http://dx.doi.org/10.1073/pnas.1519389113.

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Skp1–Cul1–F-box (SCF) E3 ligases play key roles in multiple cellular processes through ubiquitination and subsequent degradation of substrate proteins. Although Skp1 and Cul1 are invariant components of all SCF complexes, the 69 different human F-box proteins are variable substrate binding modules that determine specificity. SCF E3 ligases are activated in many cancers and inhibitors could have therapeutic potential. Here, we used phage display to develop specific ubiquitin-based inhibitors against two F-box proteins, Fbw7 and Fbw11. Unexpectedly, the ubiquitin variants bind at the interface of Skp1 and F-box proteins and inhibit ligase activity by preventing Cul1 binding to the same surface. Using structure-based design and phage display, we modified the initial inhibitors to generate broad-spectrum inhibitors that targeted many SCF ligases, or conversely, a highly specific inhibitor that discriminated between even the close homologs Fbw11 and Fbw1. We propose that most F-box proteins can be targeted by this approach for basic research and for potential cancer therapies.
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Marblestone, Jeffrey G., K. G. Suresh Kumar, Michael J. Eddins, Craig A. Leach, David E. Sterner, Michael R. Mattern, and Benjamin Nicholson. "Novel Approach for Characterizing Ubiquitin E3 Ligase Function." Journal of Biomolecular Screening 15, no. 10 (September 23, 2010): 1220–28. http://dx.doi.org/10.1177/1087057110380456.

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The ubiquitin-proteasome system is central to the regulation of numerous cellular events, and dysregulation may lead to disease pathogenesis. E3 ubiquitin ligases typically function in concert with E1 and E2 enzymes to recruit specific substrates, thereby coordinating their ubiquitylation and subsequent proteasomal degradation or cellular activity. E3 ligases have been implicated in a wide range of pathologies, and monitoring their activity in a rapid and cost-effective manner would be advantageous in drug discovery. The relative lack of high-throughput screening (HTS)–compliant E3 ligase assays has significantly hindered the discovery of E3 inhibitors. Herein, the authors describe a novel HTS-compliant E3 ligase assay platform that takes advantage of a ubiquitin binding domain’s inherent affinity for polyubiquitin chains, permitting the analysis of ubiquitin chain formation in an E3 ligase-dependent manner. This assay has been used successfully with members of both the RING and HECT families, demonstrating the platform’s broad utility for analyzing a wide range of E3 ligases. The utility of the assay platform is demonstrated by the identification of inhibitors of the E3 ligase CARP2. As the number of E3 ligases associated with various disease states increases, the ability to quantitate the activity of these enzymes in an expeditious manner becomes imperative in drug discovery.
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Tobin, Lisa A., Aaron P. Rapoport, Ivana Gojo, Maria R. Baer, Alan E. Tomkinson, and Feyruz V. Rassool. "DNA Ligase III Alpha and (Poly-ADP) Ribose Polymerase (PARP1) Are Therapeutic Targets in Imatinib-Resistant (IR) Chronic Myeloid Leukemia (CML)." Blood 114, no. 22 (November 20, 2009): 853. http://dx.doi.org/10.1182/blood.v114.22.853.853.

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Abstract Abstract 853 Therapy with the tyrosine kinase inhibitor imatinib, targeting the constitutively active BCR-ABL kinase has been remarkably successful in Philadelphia chromosome-positive (Ph+) CML, but resistance to tyrosine kinase inhibitors is a growing clinical problem, prompting the search for new therapeutic targets. BCR-ABL expression leads to increased reactive oxygen species (ROS), repair errors and genomic instability. We have previously shown that an error-prone alternative non-homologous end-joining (ALT NHEJ) pathway involving PARP1 and DNA ligase IIIa/XRCC1 is upregulated in Ph+ CML, providing a mechanism for the repair errors and genomic instability. To determine whether ALT NHEJ components may be novel therapeutic targets in IR CML, we characterized two IR cell lines (P210Mo7eIR, Baf3P210IR) for DSB repair abnormalities. Both IR cell lines demonstrate significantly higher levels of DSBs and NHEJ abnormalities (P<0.05) compared with their imatinib-sensitive (IS) counterparts. Notably, whereas steady state levels of the ALT NHEJ components DNA ligase IIIa and PARP1 are increased in IS P210Mo7e and Baf3P210 cells, compared with parental Mo7e and Baf3, the levels of these proteins are increased even further in the IR cells. Presence of increased DNA ligase IIIa and PARP1 levels in the IR cell lines suggests that these enzymes may be targets for therapy using the DNA ligase inhibitors that we have previously identified and PARP1 inhibitors, which have been used successfully in the treatment of cancers with DSB repair defects. Initial tests for cytotoxicity in BCR-ABL-positive cell lines and parental controls showed that the DNA ligase inhibitor L67, which specifically inhibits DNA ligase I and IIIα, is cytotoxic in BCR-ABL-positive cells and parental controls at concentrations of >10 μM, and that cytotoxicity is not influenced by BCR-ABL1 expression. Therefore, we examined the effect of a subtoxic concentration of L67 (0.3 μM) in the presence or absence of the PARP1 inhibitor Nu1025 (Calbiochem) at 50 μM in IR versus IS and parental cells. Combined treatment with L67 and Nu1025 significantly (p<0.001) reduces survival of IR cells compared with IS and parental controls, which were not significantly affected. To determine whether cells from CML patients that are resistant to imatinib are also sensitive to the combination of DNA ligase and PARP inhibitors, we next tested primary bone marrow mononuclear cells (BM MNC) from 6 CML patients with IR disease, compared with normal BM MNC. Cells from 3 of the 6 patients demonstrated a significant decrease in colony survival in response to the combination of DNA repair inhibitors, similar to the sensitivity demonstrated by the two IR cell lines studied. Interestingly, the patient demonstrating the highest sensitivity to the combination of DNA repair inhibitors had significantly increased levels of both DNA ligase IIIa and PARP1, whereas patients demonstrating less sensitivity had increased levels of either DNA ligase IIIa or PARP1, compared with normal BM MNC. Importantly, sensitivity to the DNA repair inhibitors is not correlated with mutations in BCR-ABL because the BCR-ABL mutation T315I that is found in Baf3P210IR cells when overexpressed in Baf3 cells has no effect on colony survival following drug treatment. Together, our results suggest that the process of acquiring IR may select for cells with high levels of PARP1 and DNA ligase IIIa and/or may upregulate ALT NHEJ pathways. Thus, patients with high levels of these proteins are likely to benefit from therapy using inhibitors of ALT NHEJ. Disclosures: No relevant conflicts of interest to declare.
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TAN, Ghee T., Sangkook LEE, Ik-Soo LEE, Jingwen CHEN, Pete LEITNER, Jeffrey M. BESTERMAN, Douglas A. KINGHORN, and John M. PEZZUTO. "Natural-product inhibitors of human DNA ligase I." Biochemical Journal 314, no. 3 (March 15, 1996): 993–1000. http://dx.doi.org/10.1042/bj3140993.

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Enzymic activity mediated by recombinant human DNA ligase I (hLI), in conjunction with tannin removal procedures, has been applied to a natural-product screen involving ~1000 plant extracts and various pure compounds. The primary hLI activity assay involved the measurement of the amount of radiolabelled phosphate in a synthetic nucleic acid hybrid that becomes resistant to alkaline phosphatase as a result of ligation. A bioactivity-guided fractionation scheme resulted in the isolation of ursolic [IC50 = 100 μg/ml (216 μM)] and oleanolic [IC50 = 100 μg/ml (216 μM)] acids from Tricalysia niamniamensis Hiern (Rubiaceae), which demonstrated similar DNA ligase inhibition profiles to other triterpenes such as aleuritolic acid. Protolichesterinic acid [IC50 = 6 μg/ml (20 μM)], swertifrancheside [IC50 = 8 μg/ml (11 μM)] and fulvoplumierin [IC50 = 87 μg/ml (357 μM)] represent three additional natural-product structural classes that inhibit hLI. Fagaronine chloride [IC50 = 10 μg/ml (27 μM)] and certain flavonoids are also among the pure natural products that were found to disrupt the activity of the enzyme, consistent with their nucleic acid intercalative properties. Further analyses revealed that some of the hLI-inhibitory compounds interfered with the initial adenylation step of the ligation reaction, indicating a direct interaction with the enzyme protein. However, in all cases, this enzyme–inhibitor interaction did not disrupt the DNA relaxation activity mediated by hLI. These results indicate that, although the same enzyme active site may be involved in both enzyme adenylation and DNA relaxation, inhibitors may exert allosteric effects by inducing conformational changes that disrupt only one of these activities. Studies with inhibitors are important for the assignment of specific cellular functions to these enzymes, as well as for their development into clinically useful antitumour agents.
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Goldenberg, Seth J., Jeffrey G. Marblestone, Michael R. Mattern, and Benjamin Nicholson. "Strategies for the identification of ubiquitin ligase inhibitors." Biochemical Society Transactions 38, no. 1 (January 19, 2010): 132–36. http://dx.doi.org/10.1042/bst0380132.

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Dysregulation of the UPS (ubiquitin–proteasome system) has been implicated in a wide range of pathologies including cancer, neurodegeneration and viral infection. Inhibiting the proteasome has been shown to be an effective therapeutic strategy in humans; however, toxicity with this target remains high. E3s (Ub–protein ligases) represent an alternative attractive therapeutic target in the UPS. In this paper, we will discuss current platforms that report on E3 ligase activity and can detect E3 inhibitors, and underline the advantages and disadvantages of each approach.
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Mills, Scott D., Ann E. Eakin, Ed T. Buurman, Joseph V. Newman, Ning Gao, Hoan Huynh, Kenneth D. Johnson, et al. "Novel Bacterial NAD+-Dependent DNA Ligase Inhibitors with Broad-Spectrum Activity and Antibacterial EfficacyIn Vivo." Antimicrobial Agents and Chemotherapy 55, no. 3 (December 28, 2010): 1088–96. http://dx.doi.org/10.1128/aac.01181-10.

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ABSTRACTDNA ligases are indispensable enzymes playing a critical role in DNA replication, recombination, and repair in all living organisms. Bacterial NAD+-dependent DNA ligase (LigA) was evaluated for its potential as a broad-spectrum antibacterial target. A novel class of substituted adenosine analogs was discovered by target-based high-throughput screening (HTS), and these compounds were optimized to render them more effective and selective inhibitors of LigA. The adenosine analogs inhibited the LigA activities ofEscherichia coli,Haemophilus influenzae,Mycoplasma pneumoniae,Streptococcus pneumoniae, andStaphylococcus aureus, with inhibitory activities in the nanomolar range. They were selective for bacterial NAD+-dependent DNA ligases, showing no inhibitory activity against ATP-dependent human DNA ligase 1 or bacteriophage T4 ligase. Enzyme kinetic measurements demonstrated that the compounds bind competitively with NAD+. X-ray crystallography demonstrated that the adenosine analogs bind in the AMP-binding pocket of the LigA adenylation domain. Antibacterial activity was observed against pathogenic Gram-positive and atypical bacteria, such asS. aureus,S. pneumoniae,Streptococcus pyogenes, andM. pneumoniae, as well as against Gram-negative pathogens, such asH. influenzaeandMoraxella catarrhalis. The mode of action was verified using recombinant strains with altered LigA expression, an Okazaki fragment accumulation assay, and the isolation of resistant strains withligAmutations.In vivoefficacy was demonstrated in a murineS. aureusthigh infection model and a murineS. pneumoniaelung infection model. Treatment with the adenosine analogs reduced the bacterial burden (expressed in CFU) in the corresponding infected organ tissue as much as 1,000-fold, thus validating LigA as a target for antibacterial therapy.
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Dissertations / Theses on the topic "Ligase I Inhibitors"

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Dickens, Michael. "Small molecule inhibitors of Mdm2 E3 ubiquitin ligase activity." Thesis, University of Nottingham, 2011. http://eprints.nottingham.ac.uk/11960/.

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Half of cancers retain wild type p53 but have alterations in the pathways involved in p53 regulation. Murine double minute 2 (Mdm2) regulates p53 by acting as an E3 ubiquitin ligase, which tags p53 for degradation through the proteasome. A small molecule inhibitor, a 5-deazaflavin analogue, has previously been identified by high throughput screening to inhibit Mdm2 E3 ubiquitin ligase activity, thereby reactivating apoptotic function of p53 selectively in cancer cells. Ninety 5-deazaflavin analogues have been synthesised by an optimized existing method and a novel method of synthesis, using the required 6-anilinouracil and 2-p-toluenesulfonyloxybenzaldehyde.The biological ability of the 5-deazaflavin analogues to act as inhibitors of Mdm2 E3 ubiquitin ligase activity to reactivate p53 has been ascertained. A new quantitative biological assay was developed, by scientists based at the Beatson Institute, for 5-deazaflavin compounds, showing excellent inhibition of Mdm2 E3 ubiquitin ligase activity on the previous qualitative biological assay, to yield IC50 data. The biological results have established a clear and logical structure-activity relationship comprising of an electron-withdrawing hydrophobic substituent at the nine position and the N10 phenyl being a prerequisite for activity as a Mdm2 inhibitor. Also meta substitution of the N10 phenyl improves activity against Mdm2 E3 ubiquitin ligase activity. Hit optimization has occurred with 10-(3-chlorophenyl)-9-trifluoromethyl-5-deazaflavin being thirty times more active than the previous identified hit compound, 10-(4-chlorophenyl)-7-nitro-5-deazaflavin. Using the X-ray crystal structure of the Mdm2/MdmX heterodimer, an improved understanding of how Mdm2 acts as an E3 ubiquitin ligase is described and used to form a hypothesis of how 5-deazaflavin analogues function as inhibitors of Mdm2. The work suggests the principle that small molecular weight compounds can inhibit E3 ubiquitin ligases as a possible anti-cancer therapy, and provide the foundation and framework for additional studies and investigation in a new and developing field of medicinal chemistry.
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Cressina, Elena. "Inhibitors for the tRNA dependent ligase MurM from streptococcus pneumoniae." Thesis, University of Warwick, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491471.

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The FemABX family of peptide ligases comprises enzymes responsible for the branching of peptidoglycan peptide part. In particular, MurM from the bacterium S. pneu11loniae is responsible for the transfer of L-alanine or L-serine from tRNA to the lysine side chain of the peptidoglycan precursor Lipid 2. MurM, and the members of the FemABX family, have been proven by genetic experiments to be essential for the development of antibiotic resistance in pathogenic bacteria and in some cases for the life of the cell itself, and therefore they constitute a new range of targets for the development of narrow spectrum antibiotics against highly resistant strains of pathogens. Inhibitors of this class of enzymes might act as efficient antibiotics, in synergy with ~-lactams, causing cell lysis. During the course of this research project, a series of S. pneu11loniae MurM inhibitors have been designed, synthesised and tested. The design of MurM inhibitors was based on the transition state analogue approach and two generations of organophosphorus derivatives have been synthesised. The first was based on a I-amino phosphonamide moiety, functionalised with simple alkyl/aryl groups; the second was a series of adenosine or 2'-deoxyadenosine I-amino phosphonates. The activity of the potential inhibitors was assayed with a radiochemical assay which monitors the transfer of a radiolabelled amino acid from tRNA to Lipid 2 in the presence ofMurM. The first generation of inhibitors was inactive on MurM while in the second generation, 2'-(1-amino ethyl phosphonyl) adenosine and 3'-(l-amino ethyl phosphonyl) 2'-deoxyadenosine showed inhibitory activity on MurM, with ICso values of780 JlM and 100 JlM respectively.
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Besong, Gilbert Ebai. "Design and synthesis of D-Ala-D-Ala ligase inhibitors as novel antibacterials." Thesis, University of Leeds, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.414211.

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Liu, Ran. "Design, Synthesis and Testing of Novel Small Molecule Inhibitors of S-phase Kinase-Associated Protein 2." Thesis, The University of Sydney, 2019. http://hdl.handle.net/2123/20999.

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S-Phase Kinase-Associated Protein 2 (Skp2), an oncoprotein, is overexpressed in numerous human cancers and plays a critical role in cell cycle progression, senescence, metabolism, cancer progression and metastasis, through promoting the ubiquitination of regulatory protein substrates, such as p27KIP1, and targeting them for degradation by the 26S proteasome. Increased expression of Skp2, accompanied by decreased levels of p27KIP1, is often associated with an aggressive phenotype and poor prognosis in many cancers. This project aimed to develop small molecules which disrupt the ubiquitination ligase activity of Skp2 on p27, a process which is facilitated by the accessory protein Cks1. In silico screening of commercial compound databases, the Specs normal (approximately 539,783 compounds) and natural compounds library (approximately 721 compounds) (http://www.specs.net/), were carried out in Maestro (Schrödinger). Lead compounds (10 compounds) were selected based upon their docking scores and their physico-chemical properties. Several of the lead compounds were then synthesised and others were purchased from SPECs. Biological evaluations were carried out by cell cytotoxic assay and cell cycle assays in breast cancer and melanoma cell lines; p27 expression was also assessed in breast cell lines through Western blot studies. Compound (36), a novel small molecule synthesised in house exhibited potent GI50 values in breast cancer and melanoma cell lines, with some of the GI50 values were in the nanomolar range; e.g. in the NM179, a NRAS mutant melanoma cell line the GI50 was 5 nM. Cell cycle studies in these cell lines were not consistent and the results were not conclusive enough to conclude that this compound acts on the Skp2/p27 pathway. Nevertheless, Western blot studies in a breast cancer cell line (MDA-MB-231) did show initial change in p27/tubulin ratio and further investigation is warranted.
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Brusa, Irene <1991&gt. "Design and synthesis of E3 ligase RNF5 inhibitors as innovative strategy to trigger mutant CFTR rescue in Cystic Fibrosis." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2022. http://amsdottorato.unibo.it/10241/1/Brusa_Irene_tesi.pdf.

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In Cystic Fibrosis (CF) the deletion of phenylalanine 508 (F508del) in the CFTR anion channel is associated to misfolding and defective gating of the mutant protein. Among the known proteins involved in CFTR processing, one of the most promising drug target is the ubiquitin ligase RNF5, which normally promotes F508del-CFTR degradation. In this context, a small molecule RNF5 inhibitor is expected to chemically mimic a condition of RNF5 silencing, thus preventing mutant CFTR degradation and causing its stabilization and plasma membrane trafficking. Hence, by exploiting a virtual screening (VS) campaign, the hit compound inh-2 was discovered as the first-in-class inhibitor of RNF5. Evaluation of inh-2 efficacy on CFTR rescue showed that it efficiently decreases ubiquitination of mutant CFTR and increases chloride current in human primary bronchial epithelia. Based on the promising biological results obtained with inh-2, this thesis reports the structure-based design of potential RNF5 inhibitors having improved potency and efficacy. The optimization of general synthetic strategies gave access to a library of analogues of the 1,2,4-thiadiazol-5-ylidene inh-2 for SAR investigation. The new analogues were tested for their corrector activity in CFBE41o- cells by using the microfluorimetric HS-YFP assay as a primary screen. Then, the effect of putative RNF5 inhibitors on proliferation, apoptosis and the formation of autophagic vacuoles was evaluated. Some of the new analogs significantly increased the basal level of autophagy, reproducing RNF5 silencing effect in cell. Among them, one compound also displayed a greater rescue of the F508del-CFTR trafficking defect than inh-2. Our preliminary results suggest that the 1,2,4-thiadiazolylidene could be a suitable scaffold for the discovery of potential RNF5 inhibitors able to rescue mutant CFTRs. Biological tests are still ongoing to acquire in-depth knowledge about the mechanism of action and therapeutic relevance of this unprecedented pharmacological strategy.
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Shouksmith, Andrew Eric. "Design and synthesis of small-molecule inhibitors targeting the SCFskp2 E3 ligase and the MDMX-p53 interaction for cancer therapy." Thesis, University of Newcastle upon Tyne, 2014. http://hdl.handle.net/10443/2904.

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The SKP1-Cullin1-F-box (SCF) E3 ligases promote the ubiquitination and proteasomemediated degradation of regulatory proteins. Subunits of the SCF complex have shown oncogenic activity, including the F-box protein S-phase Kinase-associated Protein 2 (SKP2). The SCFSKP2 E3 ligase targets several cell cycle negative regulators, e.g. p27, enabling replicative immortality. The only marketed drug that targets the ubiquitinproteasome system is Bortezomib (Velcade; Millenium Pharmaceuticals) (15), which is used to treat multiple myeloma, but has numerous side effects, as the result of targeting a proteasome involved in the regulation of multiple proteins. Targeting an F-box protein is an attractive solution because the F-box protein defines E3 ligase selectivity and each E3 ligase regulates fewer proteins. To date, no small molecule targeting an F-box protein has entered clinical trials. A recently reported compound, (((3-(2,2- dimethyltetrahydro-2H-pyran-4-yl)-4-phenylbutyl)amino)methyl)-N,N-dimethylaniline (16a), has shown evidence to suggest it inhibits the SCFSKP2 ligase. The synthesis of 16a (diastereoisomeric mixture) was completed at Newcastle University and growth inhibitory activity was confirmed in HeLa cells using a sulforhodamine B assay. Both enantiomers of N,N-dimethyl-4-(((4-phenyl-3-(tetrahydro-2H-pyran-4- yl)butyl)amino)methyl)aniline (68a) were synthesised, in one of the first documented enantioselective syntheses of a molecule of this chemotype, and demonstrated similar growth inhibitory activity in HeLa cells to each other and to the racemate, suggesting the compounds have a non-specific mechanism of action. ID HeLa GI50 (μM) 68a 27 ± 4 (S)-68a 33 ± 4 (R)-68a 29 ± 2 vi Murine double minute 2 (MDM2) and its structurally related homologue MDMX (MDM4) negatively regulate the protein level and transcriptional activity of the tumour suppressor p53. Overexpression of MDM2 and MDMX has been observed in multiple human cancers and is associated with cell immortality. Co-crystallisation of the p53-MDM2 and p53-MDMX complexes showed that three p53 residues (F19, W23 and L26) are critical to the formation of these dimers and smallmolecule inhibitors function by competitively blocking the p53-binding sites on MDM2 or MDMX. Several small-molecule MDM2 inhibitors have entered clinical trials; however, no small-molecule MDMX inhibitor has reached the same stage. A recently discovered series of 2,4-disubstituted thiazoles have shown modest potency against MDM2 and MDMX. In silico modelling suggested the compounds interacted with the p53-binding domains in both proteins and extensive SAR studies around 4-(2-((4- fluorobenzyl)amino)thiazol-4-yl)benzene-1,2-diol (59a) were conducted. This series was extended to include benzenoid and pyrrole-based compounds, including 2’-(4- chlorophenoxy)-3’-((4-fluorophenyl)amino)-[1,1’-biphenyl]-4-ol (138c) and 2-(4- chlorobenzyl)-1-(4-chlorophenyl)-5-(4-fluorophenyl)-1H-pyrrole-3-carboxylic acid (220c). All three chemotypes demonstrated low micromolar activity against MDMX and MDM2 by ELISA. ID MDMX IC50 (μM) MDM2 IC50 (μM) 59a 24.7 12.1 138c 19.0 23.2 220c 14.6 11.2 Current efforts are focussing on potentiating MDMX potency in each of the above chemotypes and trialling various co-crystallisation conditions so as to understand the molecules’ binding mechanism and guide rational drug design.
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SABBIONI, SIMONE. "CHARACTERIZATION OF THE MOLECULAR MECHANISM RESPONSIBLE FOR THE LOSS OF THE TUMOR SUPPRESSOR NUMB IN BREAST CANCER." Doctoral thesis, Università degli Studi di Milano, 2019. http://hdl.handle.net/2434/609517.

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The tumor suppressor protein, Numb, safeguards against the emergence of cancer stem cells (CSCs) in the mammary gland by ensuring homeostasis of the stem cell (SC) compartment and proper progenitor maturation. Upon its downregulation, expansion of the mammary SC compartment accompanied by the acquisition of tumorigenic potential ensues, highlighting the potent tumor suppressor function of Numb in breast cancer. Indeed, Numb loss occurs in ~30% of human breast cancers and correlates with biological aggressiveness and poor prognosis. Notably, restoration of Numb expression curbs tumorigenic potential of Numb-deficient breast cancers through the selective targeting of CSCs. Thus, the development of therapeutic strategies capable of restoring Numb expression in breast cancer could present new treatment opportunities. A well-established mechanism responsible for Numb loss in BC is its excessive polyubiquitination and consequent proteasomal degradation. Thus, it has been proposed that deregulation of the ubiquitin-proteasome system (UPS) could underlie Numb loss. The identification of the UPS machinery responsible for Numb loss would not only provide clues as to the underlying lesions in Numb-deficient cancers, but could pave the way to the development of novel strategies to restore Numb expression. In our lab, through a siRNA-based high-throughput screening of the ubiquitination machinery, we previously identified the RING-type E3 ligase, RBX1, and the F-BOX protein, FBXW8, as determinants of Numb degradation. The involvement of these proteins was validated in established BC cell lines through high-resolution studies. Notably, RBX1 and FBXW8 are components of multiprotein E3-ligase complexes, Cullin RING Ligases (CRLs). Based on these observations, the founding hypothesis of this thesis is that deregulation of an RBX1-FBXW8 CRL complex could be responsible for Numb loss in BC, and, thus, represent a potential target for therapeutic intervention in Numb-deficient tumors. Here, we initially generated Numb-deficient (MDA-MB-361) and -proficient (MDA-MB-231) cell lines stably expressing doxycycline-inducible shRNA against candidate Numb regulators. This genetic tool enabled us to achieve the in vitro and in vivo conditional ablation of RBX1 or FBXW8, thus mimicking the administration of putative drugs inhibiting specifically CRL component activity. We exploited this tool to determine the impact of RBX1 and FBXW8 silencing on the formation of outgrowths in in vitro 3D Matrigel organotypic culture: a widely used proxy of in vivo tumorigenesis. We demonstrated that the downmodulation of CRL components led to Numb restoration and impaired tumorigenic potential in vitro, selectively in Numb-deficient 3D outgrowths. We next used pre-clinical in vivo models based on orthotopic xenografts of Numb-deficient and -proficient cells to elucidate the therapeutic value of targeting the components of the UPS system. We showed that doxycycline-induced RBX1 and FBXW8 ablation curbed tumor growth selectively in Numb-deficient models, recapitulating the effects achieved upon proteasome inhibition in vivo (e.g., with Bortezomib). To investigate whether this inhibition of in vivo tumor growth was strictly dependent on Numb protein restoration, Numb-deficient cells expressing doxycycline-inducible shRNA against Numb were used as genetic tool to prevent Numb rescue upon proteasome inhibitor treatment. We showed that Numb conditional ablation induced resistance to Bortezomib treatment. We further demonstrated in vitro that the more specific Cullin ligase inhibitor, MLN4924, successfully recapitulated the effects of Bortezomib on Numb rescue in Numb-deficient model cells. Overall, the results of this thesis argue for the involvement of a CRL complex, composed of RBX1 and FBXW8, in the excessive ubiquitination of Numb in Numb-deficient breast cancers. Through pre-clinical in vivo models we have also provided proof-of-principle of the therapeutic value of targeting the UPS machinery directly involved in Numb hyperdegradation. In particular, we have identified two potential drugs, already in clinical use or under clinical development (Bortezomib and MLN4924, respectively), which could eventually be repositioned towards the treatment of Numb-deficient breast cancers.
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Gutierrez, Jemy A. "Inhibition and functional characterization of asparagine synthetase." [Gainesville, Fla.] : University of Florida, 2006. http://purl.fcla.edu/fcla/etd/UFE0015619.

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Kaur, Loveleen. "Developing as assay to screen inhibitors for various ATP-dependent ligases." Thesis, University of Westminster, 2009. https://westminsterresearch.westminster.ac.uk/item/90xxw/developing-as-assay-to-screen-inhibitors-for-various-atp-dependent-ligases.

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DNA ligases (EC.6.5.1.1) are key enzymes that catalyze the formation of phosphodiester bonds at single-stranded or double-stranded breaks between adjacent 5’-PO4 and 3’-OH groups of DNA. These enzymes are essential guardians of genomic integrity and have recently been drawing a lot of attention as novel therapeutic targets in anti-bacterial and anticancer therapies. A novel, non-electrophoretic assay method, based on the strength of interaction of the oligonucleotides with Q-sepharose (a strong anion exchanger), was developed to screen inhibitors of DNA ligases from natural product pools as well as chemical libraries. The binding affinities to Q-sepharose resin of a nicked DNA substrate (created from a 30-mer hairpin oligonucleotide and complementary 32P-labelled 6-mer oligonucleotide) and its sealed, ligated product (36-mer) were determined. Initial optimisation studies were performed with T4 DNA ligase, PBCV-1 DNA ligase and a catalytically active form of human DNA ligase I in the presence of doxorubicin (inhibitor of ATP-dependent ligases). These results when analysed in parallel between the conventional electrophoretic assay and the labelled nick-sealing assay showed that the newly developed assay is a reliable non-electrophoretic method in identifying potent DNA ligase inhibitors. The feasibility of the assay was tested in screening a collection of whole cell mass extracts, obtained from a natural product library from Basidiomycetes, in 96-well format. A novel single DNA ligase was identified, expressed and characterised from Trichomonas vaginalis (TV), a pathogenic protozoan parasite. Protein sequence analysis of TV DNA ligase indicates a strong sequence similarity to DNA ligase I homologues. The activity of recombinant TV DNA ligase I (TVlig) was investigated using protein expressed in E.coli cells. The TVlig gene product is 76 kDa and showed optimal ligation activity on a nicked DNA substrate at pH 7-8 in the presence of 1 mM ATP and (8- 20) mM MgCl2 at 30-38oC. The inhibition of the only DNA ligase present in T. vaginalis might suggest for a rational approach to stop replication and hence propagation of the parasite during infection.
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Chobotova, Katya. "Ligand binding determinants of LIF receptor." Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244596.

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Books on the topic "Ligase I Inhibitors"

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Helmsen, Sabine. Protein-Ligand-, Protein-Inhibitor- und Protein-Protein-Wechselwirkungen. Wiesbaden: Springer Fachmedien Wiesbaden, 2020. http://dx.doi.org/10.1007/978-3-658-30151-4.

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Hyŏmnyŏktan, Koryŏ Taehakkyo Sanhak. E3, ubiquitin ligase chŏhaeje rŭl wihan E1-E2-E3-substrate cognate pair network chŏngnip kisul kaebal kwa i rŭl iyong han tanangsŏng sinjŭnghugun (ADPKD) ch'iryoje kaebal yŏn'gu =: Study on E1-E2-E3-substrate cognate pair network for E3 ligase inhibitor and application. [Seoul]: Pogŏn Pokchi kajokpu, 2008.

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J, Beuth, and Pulverer Gerhard, eds. Lectin blocking: New strategies for the prevention and therapy of tumor metastasis and infectious diseases : proceedings of the Intern. Symposium Otzenhausen, May 8-9, 1993. Stuttgart ; New York: Fischer, 1994.

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Stefanis, Leonidas, and J. N. Keller. Proteasome in Neurodegeneration. Springer London, Limited, 2007.

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(Editor), Leonidas Stefanis, and J. N. Keller (Editor), eds. The Proteasome in Neurodegeneration. Springer, 2006.

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Rashwan, Hesham. Studies on inhibition of GMP synthetase and MTA phosphorylase. 1986.

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Helmsen, Sabine. Protein-Ligand-, Protein-Inhibitor- und Protein-Protein-Wechselwirkungen: Einsatz analytischer Methoden zu deren Bestimmung. Springer Spektrum, 2020.

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Book chapters on the topic "Ligase I Inhibitors"

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Mattern, Michael R., Michael J. Eddins, Saket Agarwal, David E. Sterner, Matthew P. Kodrasov, K. G. Suresh Kumar, Jian Wu, and Benjamin Nicholson. "Proteasome Inhibitors Versus E3 Ligase Inhibitors for Cancer Therapy." In Resistance to Targeted Anti-Cancer Therapeutics, 291–316. Cham: Springer International Publishing, 2014. http://dx.doi.org/10.1007/978-3-319-06752-0_12.

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Fu, Xiaoli, Jie Chu, Yuyin Li, Shasha Wang, Jie Zhou, Yujie Dai, and Aipo Diao. "Design, Synthesis, and Biological Evaluation of Nedd4 E3 Ubiquitin Ligase Small Molecule Inhibitors." In Proceedings of the 2012 International Conference on Applied Biotechnology (ICAB 2012), 1821–28. Berlin, Heidelberg: Springer Berlin Heidelberg, 2013. http://dx.doi.org/10.1007/978-3-642-37925-3_195.

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Martin, David P., David T. Puerta, and Seth M. Cohen. "Metalloprotein Inhibitors." In Ligand Design in Medicinal Inorganic Chemistry, 375–403. Chichester, UK: John Wiley & Sons, Ltd, 2014. http://dx.doi.org/10.1002/9781118697191.ch14.

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Sayers, Thomas J. "TNF-Related Apoptosis-Inducing Ligand (TRAIL)." In Proteasome Inhibitors in Cancer Therapy, 181–91. Totowa, NJ: Humana Press, 2004. http://dx.doi.org/10.1007/978-1-59259-794-9_15.

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Kos, J., V. Arbanas, V. Turk, and A. V. Maksimenko. "Chicken egg white cystatin as a ligand for affinity chromatography." In Cysteine Proteinases and their Inhibitors, edited by Vito Turk, 569–76. Berlin, Boston: De Gruyter, 1986. http://dx.doi.org/10.1515/9783110846836-053.

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Liang, Shuguang, Wei Xu, Kurumi Y. Horiuchi, Yuan Wang, and Haiching Ma. "Chemical Microarrays: A New Tool for Discovery Enzyme Inhibitors." In Ligand-Macromolecular Interactions in Drug Discovery, 149–60. Totowa, NJ: Humana Press, 2009. http://dx.doi.org/10.1007/978-1-60761-244-5_9.

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Watanabe, Nobumoto, and Hiroyuki Osada. "CHAPTER 5. Small Molecule Inhibitors of E3 Ubiquitin Ligases." In Protein–Protein Interaction Regulators, 109–23. Cambridge: Royal Society of Chemistry, 2020. http://dx.doi.org/10.1039/9781788016544-00109.

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Helmsen, Sabine. "Einleitung und Zielsetzung." In Protein-Ligand-, Protein-Inhibitor- und Protein-Protein-Wechselwirkungen, 1–2. Wiesbaden: Springer Fachmedien Wiesbaden, 2020. http://dx.doi.org/10.1007/978-3-658-30151-4_1.

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Helmsen, Sabine. "Theoretischer Hintergrund." In Protein-Ligand-, Protein-Inhibitor- und Protein-Protein-Wechselwirkungen, 3–22. Wiesbaden: Springer Fachmedien Wiesbaden, 2020. http://dx.doi.org/10.1007/978-3-658-30151-4_2.

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Helmsen, Sabine. "Praktische Arbeiten." In Protein-Ligand-, Protein-Inhibitor- und Protein-Protein-Wechselwirkungen, 23–32. Wiesbaden: Springer Fachmedien Wiesbaden, 2020. http://dx.doi.org/10.1007/978-3-658-30151-4_3.

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Conference papers on the topic "Ligase I Inhibitors"

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Scotti, Francesca, Sanjib Bhakta, and John P. Malkinson. "Lasso Peptides and Murein Peptide Ligase Inhibitors as Novel Anti-Mycobacterial Agents." In The 24th American Peptide Symposium. Prompt Scientific Publishing, 2015. http://dx.doi.org/10.17952/24aps.2015.193.

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Shukla, Shirish, Qingjie Zhao, Weijang Ying, Felicia Gray, Kelly Vandenberg, George Lund, Bohdan Boytsov, Shihan He, Jolanta Grembecka, and Tomasz Cierpicki. "Abstract 3520: Small molecule inhibitors of ring1B-Bmi1 E3 ligase target polycomb repressive complex 1 activity and regulate cell proliferation." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-3520.

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Tseng, Hui-Min, David Shum, Hakim Djaballah, and David Scheinberg. "Abstract 3689: Identification of DNA ligase IV inhibitors as possible drug and probe candidates for enhancement of radiation treatment and chemotherapy." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-3689.

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Li, Hua, Elizabeth Umeda, Yingjie Song, Denise Young, Lakshmi Ravindranath, Ahmed Mohamed, Shashwat Sharad, et al. "Abstract 4679: Silencing of PMEPA1, a NEDD4 E3 ubiquitin ligase binding protein, stabilizes androgen receptor and confers resistance to AR inhibitors." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-4679.

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Daubriac, Julien, Jonathan Melamed, Unnati Pandya, Harvey I. Pass, and Leslie I. Gold. "Abstract LB-068: Inhibitors of Skp2 E3 ligase-mediated degradation of p27kip1 as a novel therapeutic approach to malignant pleural mesothelioma." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-lb-068.

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Egbuta, Chinaza, Julien Dubrulle, Ana Tellechea, Miguel A. Manzanares, Yunfeng Li, Shanshan Duan, John K. Dickson, et al. "Abstract 5231: Small-molecule inhibitors of SCF-Skp2-Cks1 ubiquitin E3 ligase stabilize nuclear p27kip1as a novel therapeutic approach to endometrial cancer." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-5231.

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Sosin, Angela M., Angelika M. Burger, Dajun Yang, Ramzi M. Mohammad, and Ayad Al-Katib. "Abstract 4516: A new class of MDM2 inhibitors cause growth inhibition and stabilize wt p53 in lymphoma cells but do not interfere with MDM2 E3 ligase activity." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-4516.

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Kheraldine, Hadeel, Ishita Gupta, Farhan Cyprian, Semir Vranic, and Ala-Eddin Al Moustafa. "The Combination of Dasatinib and PD L1 inhibitor prevents the progression of epithelial mesenchymal transition and dramatically blocks cell invasion of HER2 positive breast cancer cells." In Qatar University Annual Research Forum & Exhibition. Qatar University Press, 2021. http://dx.doi.org/10.29117/quarfe.2021.0105.

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Introduction: Both Dasatinib (DA), a tyrosine kinase inhibitor that is used for targeted cancer therapy, and programmed death-ligand 1 (PD-1/PD-L1) inhibitor that is an immune checkpoint therapy, play a vital role in the management of several types of solid tumors, including breast. Nevertheless, the combined outcome of DA and PD-1/PD-L1 inhibitors in human carcinomas has not been explored yet. Materials and methods: We herein compared the individual impact of DA and PD-1/PD-L1 inhibitors (BMS-202) with their combination on two human HER2-positive breast cancer cell lines, SKBR3 and ZR75. Results: Our data revealed that the combination of DA and BMS-202 significantly inhibits cell proliferation in both cell lines as compared to mono treatment and/or untreated cells. Moreover, we observed that combination treatment prevents the progression of “epithelial-mesenchymal transition” (EMT), which is a hallmark of cell invasion and cancer progression. Our data reveal that DA and BMS-202 together dramatically inhibit cell invasion of SKBR3 and ZR75 cells; this is accompanied by the up-regulation of E-cadherin and its restoration along with b-catenin on the cell membrane and its undercoat, respectively, in addition to the downregulation of vimentin, which are major markers of EMT. Additionally, we found that the synergistic treatment of DA and BMS-202 inhibits colony formation of both cell lines in comparison with their matched control. Conclusion: Our findings implicate that, in comparison to monotreatment, combination of DA and BMS-202 could have a significant impact on the management of HER2-positive breast cancer via HER2 inactivation and specifically b-catenin signaling pathways.
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Mitsuuchi, Yasuhiro, Christopher A. Benetatos, Thomas Haimowitz, Yijun Deng, Angeline C. Mufalli, Martin E. Seipel, Jennifer M. Burns, Gurpreet S. Kapoor, C. Glenn Begley, and Stephen M. Condon. "Abstract 1806: Birinapant, a bivalent SMAC-mimetic, promotes efficient cellular IAP E3 ligase activity and formation of a pro-apoptotic RIPK1:caspase-8 complex while monovalent IAP inhibitors are less efficient - implications for therapeutic utility." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-1806.

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Duckworth, Benjamin P., Helena I. Boshoff, Clifton E. Barry, and Courtney C. Aldrich. "Design of a nucleoside inhibitor of biotin protein ligase from Mycobacterium tuberculosis." In XVth Symposium on Chemistry of Nucleic Acid Components. Prague: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 2011. http://dx.doi.org/10.1135/css201112199.

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Reports on the topic "Ligase I Inhibitors"

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Guo, Lijuan, Xiaoyi Lin, Xin Lin, Yulei Wang, Jiali Lin, Yi Zhang, Xiangqing Chen, Miao Chen, Guochun Zhang, and Yifang Zhang. Risk of Interstitial Lung Disease With Use of Programmed Cell Death 1 Inhibitors versus Programmed Cell Death Ligand 1 Inhibitors In Breast Cancer: A meta-analysis and Cases description. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, June 2023. http://dx.doi.org/10.37766/inplasy2023.6.0007.

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Matsuyama, Shigemi. Apoptosis Induction by Targeting Interferon Gamma Receptor 2 (IFNgammaR2) in Prostate Cancer: Ligand (IFNgamma)-Independent Novel Function of IFNgammaR2 as a Bax Inhibitor. Fort Belvoir, VA: Defense Technical Information Center, August 2014. http://dx.doi.org/10.21236/ada611816.

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Matsuyama, Shigemi. Apoptosis Induction by Targeting Interferon Gamma Receptor 2 (IFNgammaR2) in Prostate Cancer: Ligand (IFNgamma)-Independent Novel Function of IFNgammaR2 as a Bax Inhibitor. Fort Belvoir, VA: Defense Technical Information Center, August 2013. http://dx.doi.org/10.21236/ada591011.

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Matsuyama, Shigemi. Apoptosis Induction by Targeting Interferon Gamma Receptor 2 (IFNgammaR2) in Prostate Cancer: Ligand (IFNgamma)-Independent Novel Function of IFNgammaR2 as a Bax Inhibitor. Fort Belvoir, VA: Defense Technical Information Center, August 2015. http://dx.doi.org/10.21236/ada623598.

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Liu, Shu, Xin Zhang, Wenhan Yang, and Shun Xu. Association of Patient Sex with Efficacy of Programmed Death-1/Ligand-1 Inhibitors in Advanced Non–small-cell Lung Cancer: A Systematic Review and Meta-analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, January 2021. http://dx.doi.org/10.37766/inplasy2021.1.0005.

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Altstein, Miriam, and Ronald J. Nachman. Rational Design of Insect Control Agent Prototypes Based on Pyrokinin/PBAN Neuropeptide Antagonists. United States Department of Agriculture, August 2013. http://dx.doi.org/10.32747/2013.7593398.bard.

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The general objective of this study was to develop rationally designed mimetic antagonists (and agonists) of the PK/PBAN Np class with enhanced bio-stability and bioavailability as prototypes for effective and environmentally friendly pest insect management agents. The PK/PBAN family is a multifunctional group of Nps that mediates key functions in insects (sex pheromone biosynthesis, cuticular melanization, myotropic activity, diapause and pupal development) and is, therefore, of high scientific and applied interest. The objectives of the current study were: (i) to identify an antagonist biophores (ii) to develop an arsenal of amphiphilic topically active PK/PBAN antagonists with an array of different time-release profiles based on the previously developed prototype analog; (iii) to develop rationally designed non-peptide SMLs based on the antagonist biophore determined in (i) and evaluate them in cloned receptor microplate binding assays and by pheromonotropic, melanotropic and pupariation in vivo assays. (iv) to clone PK/PBAN receptors (PK/PBAN-Rs) for further understanding of receptor-ligand interactions; (v) to develop microplate binding assays for screening the above SMLs. In the course of the granting period A series of amphiphilic PK/PBAN analogs based on a linear lead antagonist from the previous BARD grant was synthesized that incorporated a diverse array of hydrophobic groups (HR-Suc-A[dF]PRLa). Others were synthesized via the attachment of polyethylene glycol (PEG) polymers. A hydrophobic, biostablePK/PBAN/DH analog DH-2Abf-K prevented the onset of the protective state of diapause in H. zea pupae [EC50=7 pmol/larva] following injection into the preceding larval stage. It effectively induces the crop pest to commit a form of ‘ecological suicide’. Evaluation of a set of amphiphilic PK analogs with a diverse array of hydrophobic groups of the formula HR-Suc-FTPRLa led to the identification of analog T-63 (HR=Decyl) that increased the extent of diapause termination by a factor of 70% when applied topically to newly emerged pupae. Another biostablePK analog PK-Oic-1 featured anti-feedant and aphicidal properties that matched the potency of some commercial aphicides. Native PK showed no significant activity. The aphicidal effects were blocked by a new PEGylated PK antagonist analog PK-dF-PEG4, suggesting that the activity is mediated by a PK/PBAN receptor and therefore indicative of a novel and selective mode-of-action. Using a novel transPro mimetic motif (dihydroimidazole; ‘Jones’) developed in previous BARD-sponsored work, the first antagonist for the diapause hormone (DH), DH-Jo, was developed and shown to block over 50% of H. zea pupal diapause termination activity of native DH. This novel antagonist development strategy may be applicable to other invertebrate and vertebrate hormones that feature a transPro in the active core. The research identifies a critical component of the antagonist biophore for this PK/PBAN receptor subtype, i.e. a trans-oriented Pro. Additional work led to the molecular cloning and functional characterization of the DH receptor from H. zea, allowing for the discovery of three other DH antagonist analogs: Drosophila ETH, a β-AA analog, and a dF analog. The receptor experiments identified an agonist (DH-2Abf-dA) with a maximal response greater than native DH. ‘Deconvolution’ of a rationally-designed nonpeptide heterocyclic combinatorial library with a cyclic bis-guanidino (BG) scaffold led to discovery of several members that elicited activity in a pupariation acceleration assay, and one that also showed activity in an H. zea diapause termination assay, eliciting a maximal response of 90%. Molecular cloning and functional characterization of a CAP2b antidiuretic receptor from the kissing bug (R. prolixus) as well as the first CAP2b and PK receptors from a tick was also achieved. Notably, the PK/PBAN-like receptor from the cattle fever tick is unique among known PK/PBAN and CAP2b receptors in that it can interact with both ligand types, providing further evidence for an evolutionary relationship between these two NP families. In the course of the granting period we also managed to clone the PK/PBAN-R of H. peltigera, to express it and the S. littoralis-R Sf-9 cells and to evaluate their interaction with a variety of PK/PBAN ligands. In addition, three functional microplate assays in a HTS format have been developed: a cell-membrane competitive ligand binding assay; a Ca flux assay and a whole cell cAMP ELISA. The Ca flux assay has been used for receptor characterization due to its extremely high sensitivity. Computer homology studies were carried out to predict both receptor’s SAR and based on this analysis 8 mutants have been generated. The bioavailability of small linear antagonistic peptides has been evaluated and was found to be highly effective as sex pheromone biosynthesis inhibitors. The activity of 11 new amphiphilic analogs has also been evaluated. Unfortunately, due to a problem with the Heliothis moth colony we were unable to select those with pheromonotropic antagonistic activity and further check their bioavailability. Six peptides exhibited some melanotropic antagonistic activity but due to the low inhibitory effect the peptides were not further tested for bioavailability in S. littoralis larvae. Despite the fact that no new antagonistic peptides were discovered in the course of this granting period the results contribute to a better understanding of the interaction of the PK/PBAN family of Nps with their receptors, provided several HT assays for screening of libraries of various origin for presence of PK/PBAN-Ragonists and antagonists and provided important practical information for the further design of new, peptide-based insecticide prototypes aimed at the disruption of key neuroendocrine physiological functions in pest insects.
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Altstein, Miriam, and Ronald Nachman. Rationally designed insect neuropeptide agonists and antagonists: application for the characterization of the pyrokinin/Pban mechanisms of action in insects. United States Department of Agriculture, October 2006. http://dx.doi.org/10.32747/2006.7587235.bard.

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The general objective of this BARD project focused on rationally designed insect neuropeptide (NP) agonists and antagonists, their application for the characterization of the mechanisms of action of the pyrokinin/PBAN (PK-PBAN) family and the development of biostable, bioavailable versions that can provide the basis for development of novel, environmentally-friendly pest insect control agents. The specific objectives of the study, as originally proposed, were to: (i) Test stimulatory potencies of rationally designed backbone cyclic (BBC) peptides on pheromonotropic, melanotropic, myotropic and pupariation activities; (ii) Test the inhibitory potencies of the BBC compounds on the above activities evoked either by synthetic peptides (PBAN, LPK, myotropin and pheromonotropin) or by the natural endogenous mechanism; (iii) Determine the bioavailability of the most potent BBC compounds that will be found in (ii); (iv) Design, synthesize and examine novel PK/PBAN analogs with enhanced bioavailability and receptor binding; (v) Design and synthesize ‘magic bullet’ analogs and examine their ability to selectively kill cells expressing the PK/PBAN receptor. To achieve these goals the agonistic and antagonistic activities/properties of rationally designed linear and BBC neuropeptide (NP) were thoroughly studied and the information obtained was further used for the design and synthesis of improved compounds toward the design of an insecticide prototype. The study revealed important information on the structure activity relationship (SAR) of agonistic/antagonistic peptides, including definitive identification of the orientation of the Pro residue as trans for agonist activity in 4 PK/PBANbioassays (pheromonotropic, pupariation, melanotropic, & hindgut contractile) and a PK-related CAP₂b bioassay (diuretic); indications that led to the identification of a novel scaffold to develop biostbiostable, bioavailable peptidomimetic PK/PBANagonists/antagonists. The work led to the development of an arsenal of PK/PBAN antagonists with a variety of selectivity profiles; whether between different PKbioassays, or within the same bioassay between different natural elicitors. Examples include selective and non-selective BBC and novel amphiphilic PK pheromonotropic and melanotropic antagonists some of which are capable of penetrating the moth cuticle in efficacious quantities. One of the latter analog group demonstrated unprecedented versatility in its ability to antagonize a broad spectrum of pheromonotropic elicitors. A novel, transPro mimetic motif was proposed & used to develop a strong, selective PK agonist of the melanotropic bioassay in moths. The first antagonist (pure) of PK-related CAP₂b diuresis in flies was developed using a cisPro mimetic motif; an indication that while a transPro orientation is associated with receptor agonism, a cisPro orientation is linked with an antagonist interaction. A novel, biostablePK analog, incorporating β-amino acids at key peptidase-susceptible sites, exhibited in vivo pheromonotropic activity that by far exceeded that of PBAN when applied topically. Direct analysis of neural tissue by state-of-the-art MALDI-TOF/TOF mass spectrometry was used to identify specific PK/PK-related peptides native to eight arthropod pest species [house (M. domestica), stable (S. calcitrans), horn (H. irritans) & flesh (N. bullata) flies; Southern cattle fever tick (B. microplus), European tick (I. ricinus), yellow fever mosquito (A. aegypti), & Southern Green Stink Bug (N. viridula)]; including the unprecedented identification of mass-identical Leu/Ile residues and the first identification of NPs from a tick or the CNS of Hemiptera. Evidence was obtained for the selection of Neb-PK-2 as the primary pupariation factor of the flesh fly (N. bullata) among native PK/PK-related candidates. The peptidomic techniques were also used to map the location of PK/PK-related NP in the nervous system of the model fly D. melanogaster. Knowledge of specific PK sequences can aid in the future design of species specific (or non-specific) NP agonists/antagonists. In addition, the study led to the first cloning of a PK/PBAN receptor from insect larvae (S. littoralis), providing the basis for SAR analysis for the future design of 2ⁿᵈgeneration selective and/or nonselective agonists/antagonists. Development of a microplate ligand binding assay using the PK/PBAN pheromone gland receptor was also carried out. The assay will enable screening, including high throughput, of various libraries (chemical, molecular & natural product) for the discovery of receptor specific agonists/antagonists. In summary, the body of work achieves several key milestones and brings us significantly closer to the development of novel, environmentally friendly pest insect management agents based on insect PK/PBANNPs capable of disrupting critical NP-regulated functions.
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