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Journal articles on the topic "Y220C":
1
Gener-Ricos, Georgina, Jan Philipp Bewersdorf, Sanam Loghavi, Aaron D. Goldberg, Christopher Famulare, Ghayas C. Issa, Gautam Borthakur, et al. "TP53 Y220C Mutations in Patients with Myeloid Malignancies." Blood 142, Supplement 1 (November 28, 2023): 1477. http://dx.doi.org/10.1182/blood-2023-189343.
Abstract:
Background: TP53 gene mutations lead to inactivation of the protein p53, causing genome instability, oncogenesis, and treatment resistance conferring an unfavorable prognosis. TP53 Y220C missense mutations in exon 6 (p.659A>G) are described as a frequent ‘hot spot’ mutation in solid tumors. A novel Y220C-targeted small molecule (PC14586) has shown preliminary efficacy and safety in patients with solid tumors (Dumbrava, E., ASCO 2022). No data has been reported about TP53 Y220C in hematologic malignancies to date. We set out to evaluate the clinicopathologic characteristics of TP53 Y220C in hematologic malignancies and particularly, myeloid neoplasms. Methods: We identified all patients with hematologic neoplasms with TP53 Y220C mutations at University of Texas MD Anderson Cancer Center and Memorial Sloan-Kettering Cancer Center, detected by standard next generation sequencing assays, and focused on patients with myeloid malignancies; summarizing the patient characteristics, disease features and outcomes for patients with this specific TP53 mutation. Overall survival (OS) was assessed by the Kaplan-Meier method from date of diagnosis to date of death from any cause or date of last follow-up. Leukemia-free survival (LFS) was calculated from time to diagnosis of TP53 Y220C mutated myelodysplastic syndrome (MDS) to date of transformation to acute myeloid leukemia (AML) or death. Survival analysis was conducted only for newly diagnosed patients with available follow-up data. Results: We identified 143 patients (pts) with hematologic malignancies harboring a TP53 Y220C mutation. MDS and AML were the most frequent diagnoses (MDS, n=66; AML, n=48). Median age was 69 years (range, 32-92) and 56% of patients were male (Table 1). We then analyzed in more detail patients with MNs, including CHIP/CCUS, MDS, AML and MDS/MPN. Among those, in 76 (64%) pts the TP53 Y220C mutation was detected at initial diagnosis and in 43 (36%) pts, TP53 Y220C was identified in the relapsed/refractory setting. Therapy-related myeloid neoplasms (MNs) accounted for 51 of 119 pts (41%). Complex karyotype was frequent (n=88/119, 74%) in the setting of TP53 Y220C. Median TP53 Y220C variant allele frequency (VAF) was 32% (range, 1%-96%). Eighty-two patients (69%) had additional co-mutations: 24 (20%) pts had additional (non-Y220C) TP53 mutations only; 34 (29%) pts had only non- TP53 co-mutations (most frequently DNMT3A and TET2) and 24 (20%) pts had additional TP53 mutations in the setting of other co-mutations. With a median follow-up of 9 months, median OS for patients with newly diagnosed TP53 Y220C MDS (n=39) and AML (n=23) was 13.1 months (95% CI, 7.6 to 18.7) and 8 months (95% CI, 5.6 to 13.4), respectively ( p=0.06) (Figure 2). For the TP53 Y220C MDS cohort, AML transformation occurred in 13 (33%) patients, after a median of 14.3 months. Median LFS for these patients was 12.2 months (95% CI, 7.9 to 16.5). Modest and non-statistically significant differences in median LFS for MDS patients who did and did not receive stem cell transplant (SCT) were identified; MDS+SCT (n=12) 14.5 months (95% CI, 4 to 25) vs MDS+no-SCT (n=27) 9.3 months (95% CI, 4.6 to 14), p=0.18. Interestingly, four patients diagnosed with TP53 Y220C mutated CHIP/CCUS with a median VAF of 2% were identified, and with a median follow-up of 34.6 months, none have developed dysplastic changes or progression to MDS or AML at the time of cut off. Additional outcomes data will be forthcoming in the analysis of this cohort of patients with TP53 Y220C mutated myeloid neoplasms. Conclusions: TP53 Y220C mutations are present in malignant blood disorders and are particularly more common in myelodysplastic syndromes and acute myeloid leukemia, with associated poor outcomes. Novel targeted therapies for this TP53 variant (Y220C) would be of interest for this patient population.
2
Carter, Bing Z., Po Yee Mak, Baozhen Ke, Yuki Nishida, Steffen Boettcher, Andrea Bedoy, Lauren B. Ostermann, et al. "Selective Targeting of TP53-Y220C Mutant AML By PC14586 Results in TP53 Wild-Type Conformation and Synergistical Apoptosis Induction By Concomitant Inhibition of Xpo-1, MDM2, or Bcl-2." Blood 142, Supplement 1 (November 28, 2023): 2261. http://dx.doi.org/10.1182/blood-2023-181186.
Abstract:
Patients with TP53-mutant acute myeloid leukemia (AML) constitute the worst outcome group with a survival of only several months. TP53 mutations frequently become dominant following exposure to chemotherapeutic agents, Bcl-2 or MDM2 inhibitors, and confer resistance to multiple other therapies. Y220C is a recurrent hotspot TP53 mutation observed in solid tumors and hematological malignancies, predominantly in AML and MDS (Gener-Ricoset al., ASH 2022). PC14586 (PMV Pharmaceuticals) is designed to bind to the p53-Y220C mutant and restore wild-type (WT) p53 protein conformation and function. PC14586 has been shown to convert Y220C-p53 mutant into WT-p53 protein conformation, induce the activation of p53 transcriptional pathways resulting in selective inhibition of proliferation ofTP53-Y220C mutant solid tumor cell lines and achieved partial responses and stable disease in an ongoing phase I clinical trial in solid tumors (Dumbrava, ASCO 2022, NCT04585750). However, the activity of PC14586 in TP53-Y220C mutated AML/MDS has not been investigated, either as monotherapy or in mechanism-based drug combinations. We investigated the mechanisms of action of PC14586 in AML using cells with TP53-WT, knockout (KO), and mutations (one allele with Y220C or R175H and the other truncated) generated by CRISPR (Boettcher et al., Science 2019) and found that PC14586 converts Y220C mutant p53 to the active form of p53 and selectively activates p53 signaling proteins including MDM2 and p21 in TP53-Y220C AML cells. PC14586 decreased cell viability but had limited apoptogenic activities in the TP53-Y220C AML cells . In primary AML cells with Y220C mutations, PC14586 induced cell death in bulk AML cells and, importantly, also in stem/progenitor cells in 2/3 samples. We reported previously that sustained nuclear retention of p53 by XPO-1 inhibition greatly enhances the transcriptional activity of activated p53 and that activation of p53 by inhibiting its negative regulator MDM2 effectively induces cell death in TP53-WT AML (Kojima et al., Blood 2013, 2005), and that XPO-1 inhibition vastly increased apoptosis induced by MDM2 inhibition through 20-60-fold increased p53 transcriptional activities. We also reported that combined Bcl-2 inhibition and p53 activation is synthetically lethal in TP53-WT AML (Pan et al., Cancer Cell 2017). We hypothesized that XPO-1 synergizes with PC14586 by retaining PC14586-activated p53 in the nucleus and that inhibition of MDM2 induced by PC14586-mediated p53 activation or inhibition of Bcl-2 synergizes with PC14586 in TP53-Y220C AML cells. Indeed, we found that PC14586-induced p53 target proteins were further upregulated when PC14586 was combined with XPO-1 or MDM2 inhibition. Inhibition of XPO-1, MDM2, or Bcl-2 synergistically induced massive apoptosis and decreased cell viability in PC14586 treated TP53 Y220C mutant AML cells (Fig.1), in primary AML blasts, and in CD34+CD38- stem/progenitor cells but not in normal bone marrow cells or stem/progenitor cells through conformational changes of mutant p53 to p53-WT. While PC14586 had limited activity on proliferation in TP53-Y220C AML cells, the combination with Bcl-2 inhibition largely blocked G1-S transition and enhanced apoptosis. The G1-S transition block and apoptosis induction were even more pronounced when PC14586 was combined with XPO-1 or MDM2 inhibitors as determined by flow cytometry measurement of DNA content, and PARP cleavage. Experiments in TP53-Y220C AML PDX models are ongoing and will be reported. In summary, PC14586 converts Y220C-mutant p53 into WT-p53 conformation and induces p53 target proteins. Mechanism-based combinations with XPO-1, MDM2, and Bcl-2 inhibitors induce massive apoptosis. PC14586 is presently in early clinical trials.
3
Puzio-Kuter, Anna M., Chris Mulligan, Brandon Russo, Amy Wiebesiek, Lizhong Xu, Hong Yang, Binh Vu, and Melissa Dumble. "Abstract 1295: Small molecule reactivators of Y220C mutant p53 modulate tumor infiltrating leukocytes and synergize with immune checkpoint inhibitors." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1295. http://dx.doi.org/10.1158/1538-7445.am2022-1295.
Abstract:
Abstract Half of human cancers possess mutations in the TP53 gene, with most clustering as hotspots in the DNA binding domain. A tyrosine to cysteine substitution at amino acid 220 of the p53 protein (Y220C) is one such hotspot mutation (~1% of all solid tumors). Small molecules that reactivate Y220C mutant p53 activity to be like wild type have been developed at PMV Pharmaceuticals and the lead compound PC14586 is in Phase I clinical development. The molecules were designed to bind tightly to a crevice within the Y220C p53 mutant protein and stabilize it to a wild type conformation allowing reactivation of p53 transcriptional activity and expression of target proteins (e.g. p21, MDM2), resulting in tumor regression in Y220C p53 mutant xenograft models grown in immunocompromised mice. p53 has been documented to contribute to immune responses by activating regulators of immune signaling pathways and to result in T-cell exclusion in tumor models. To investigate the role of p53 and the immune system in tumorigenesis, a Y220C human p53 knock-in (HUPKI) mouse was generated. Mice that are homozygous mutant for the Y220C humanized alleles succumbed to lymphomas and sarcomas within 6 months and cell lines generated from these tumors were shown to be sensitive in an in vitro proliferation assay to Y220C p53 reactivators (IC50 ~ 192-722 nM) and used to generate Y220C mutant syngeneic mouse models. Administration of Y220C p53 reactivators in Y220C p53 syngeneic mouse models resulted in a dose responsive anti-tumor effect, with maximally efficacious doses resulting in durable cures in nearly all animals, more than observed in immunocompromised mouse models. Addition of checkpoint agents with sub-efficacious administration of Y220C reactivating compounds resulted in synergistic increases in mean survival time of mice, longer than with either single agent. Immunophenotyping analysis of HUPKI Y220C mutant tumors exposed to p53 reactivator compounds showed modulation of the tumor immune environment. Changes include dose responsive increases in T-cells (CD4+, CD8+), T-regulatory cells, natural killer T cells and dose responsive decreases in macrophages (M2) and g-MDSC cells. The synergy observed with an anti-PD-1 combination appears driven by an increase in CD8+ T cells, given a decrease in efficacy in mice depleted of CD8+ T cells, following exposure to anti-CD8. Further investigation into the role of Y220C p53 reactivation in immune modulation showed decreased cytokines and chemokines involved in inflammation (i.e. CXCL10, Ccl2) and an increase in a Tumor Inflammation Signature (nanoString) in a dose and time dependent manner. Taken together, these data suggest a role for p53 signaling in encouraging an immunologically hot tumor microenvironment and provide support for testing small molecule reactivators of mutant p53 in combination with immune checkpoint inhibitors. Citation Format: Anna M. Puzio-Kuter, Chris Mulligan, Brandon Russo, Amy Wiebesiek, Lizhong Xu, Hong Yang, Binh Vu, Melissa Dumble. Small molecule reactivators of Y220C mutant p53 modulate tumor infiltrating leukocytes and synergize with immune checkpoint inhibitors [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 1295.
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Zheng, Qian, Peng Wang, Chen Liang, Yao Li, Xin Sun, Amin Li, Wei Zhang, Wei Long, and Yanping Wang. "Abstract 5940: JAB-30355: A highly potent, orally bioavailable p53-Y220C reactivator." Cancer Research 84, no. 6_Supplement (March 22, 2024): 5940. http://dx.doi.org/10.1158/1538-7445.am2024-5940.
Abstract:
Abstract Background: As a key tumor suppressor, p53 precisely regulates cellular events such as cell cycle arrest, apoptosis, senescence, and DNA repair under physiological conditions. In 50-60% of human cancers, TP53 gene is mutated. The TP53 Y220C is a hotspot loss-of-function mutation occurring in around 1% of solid tumors. Application of p53-Y220C reactivator for restoration of p53 function represents a promising treatment strategy for patients with this mutation. Methods: The Induced Allosteric Drug Discovery Platform (IADDP), which integrates medicinal chemistry, biochemical and biophysical studies, and computational techniques, was applied for the development of JAB-30355. The proportion of p53-Y220C with wild-type protein-like structure after JAB-30355 treatment was determined by immunoprecipitation. Thermal shift assay was applied to assess the thermal stability of JAB-30355-reactivated p53-Y220C protein. DNA binding assay was developed to evaluate the in vitro DNA binding activity. p53-luciferase reporter system was developed to evaluate the cellular transcriptional activity. qPCR and Western blotting were performed to evaluate the transcriptional and translational levels of p53 downstream targets, respectively. CellTiter-Glo assay was performed to evaluate the inhibitory activity of JAB-30355 on the viability of tumor cell lines harboring wild-type or Y220C mutated TP53. In vivo PK-PD study was conducted to evaluate the relationship between JAB-30355 concentration and expression of p53 target genes. Multiple CDX and PDX mouse models harboring TP53 Y220C were used to evaluate the antitumor activity of JAB-30355. Results: Immunoprecipitation assay and thermal shift assay results demonstrated that JAB-30355 efficiently restored the wild-type p53-like structure and enhanced protein stability of p53-Y220C in a dose-dependent manner. In addition, JAB-30355 significantly enhanced the DNA binding activity of p53-Y220C and subsequently increased the expression of p53 target genes, such as CDKN1A, MDM2 and PUMA. JAB-30355 inhibited cell viability of multiple TP53 Y220C-mutated cancer cell lines with IC50s ranging from 0.2 to 0.7 μM, and exhibited good selectivity against TP53 wild-type cells. Overall, the in vitro data demonstrated that JAB-30355 is a potent and selective p53-Y220C reactivator. In vivo PK-PD study showed good correlation between JAB-30355 exposure and activation of p53 target genes. Furthermore, JAB-30355 exhibited dose-dependent anti-tumor activity, inducing tumor stasis or regression in multiple CDX and PDX models of ovarian cancer, pancreatic cancer, gastric cancer, and small cell lung cancer, with overall good tolerability. Conclusions: JAB-30355 is a highly potent, selective, and orally bioavailable p53-Y220C reactivator that will be tested in clinical space soon. Citation Format: Qian Zheng, Peng Wang, Chen Liang, Yao Li, Xin Sun, Amin Li, Wei Zhang, Wei Long, Yanping Wang. JAB-30355: A highly potent, orally bioavailable p53-Y220C reactivator [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 5940.
5
Liu, Meng, Kaijun Geng, Biao Lu, Yuanfeng Xia, and Fanglong Yang. "Abstract 7275: GS-P-328, a brain-penetrant small molecule p53 Y220C reactivator for tumors harboring p53 Y220C mutation." Cancer Research 84, no. 6_Supplement (March 22, 2024): 7275. http://dx.doi.org/10.1158/1538-7445.am2024-7275.
Abstract:
Abstract As a tumor suppressor, p53 can prevent tumor development through multiple pathways. However, mutation of TP53 and the resultant inactivation of p53 allow evasion of tumor cell death and rapid tumor progression. The oncogenic Y220C mutation is the ninth most frequent p53 missense mutation in cancer. Y220C mutation creates a narrow, hydrophobic pocket on the surface of the p53 DBD that reduces its thermal stability. As a result, the Y220C mutation causes a rapidly unfold of the p53 protein under physiological conditions, abrogates p53 signaling and drives tumorigenesis. There are approximately 100,000 new Y220C mutation cancer cases per year worldwide with limited treatment choices. The initial clinical evaluation of PC14586 that can restore missense-mutant p53 protein has seen efficacy in patients harboring p53 Y220C mutation even though there is still room for improvement. Here we report a brain-penetrable, highly potent p53 Y220C reactivator which has great in vitro activity as well as induce tumor shrinkage in multiple tumor models at a much lower systematic exposure comparing to PC14586. In vitro, GS-P-328 could bind to p53 Y220C protein with a single nM potency and potently induce cell death in a wide range of p53 Y220C tumor cells while have no anti-proliferative effects with p53 WT cells. GS-P-328 is also active in patient-derived cell (PDC) models in various tumor background including SCLC, gastric, ovarian and colon. In vivo, GS-P-328, at approximately 1/3 of systematic exposure comparing to a leading clinical reactivator, causes tumor shrinkage in multiple CDX models. GS-P-328 could induce MDM2/p21 upregulation in cell systems. In vivo, GS-P-328 could induce 2 fold and more increase in MDM2/p21 protein levels in tumor tissues at approximately 1/3 of plasma concentrations comparing to PC14586. More importantly, in a NUGC3-luc intracranial model, GS-P-328 could strongly inhibit growth of cancer cells in the mouse brain. GS-P-328 has a favorable ADME profile in rodents, dogs and NHPs, as well as a much better safety profile. GS-P-328 is now under IND-enabling study and P1 study is planned in early 2025. Citation Format: Meng Liu, Kaijun Geng, Biao Lu, Yuanfeng Xia, Fanglong Yang. GS-P-328, a brain-penetrant small molecule p53 Y220C reactivator for tumors harboring p53 Y220C mutation [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 7275.
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Valenzuela-Chavira, Ignacio, Salvador Meneses-Sagrero, Aldo A. Arvizu-Flores, Javier Hernández-Paredes, Luisa Rascón-Valenzuela, Carlos A. Velázquez-Contreras, and Ramón E. Robles-Zepeda. "Molecular Docking of the Cardenolides of Asclepias subulata in the Human p53 Protein Reveals an Interaction in the Cleft of the Y220C Mutant." Current Chemical Biology 15, no. 3 (September 2021): 222–33. http://dx.doi.org/10.2174/2212796815666211026112056.
Abstract:
Background and Objective: The objective of the present study is to use docking and ADME analysis to determine if the cardenolides of Asclepias subulata are potential stabilizing drugs of the p53-Y220C mutant. Materials and Methods: Two different receptors, wild-type p53, and the mutant p53-Y220C, were used for docking. Three independent stochastic series were performed, with 60,000 poses considered, and the 30 best poses were selected. ADME analysis was performed using SwissADME. Results: Docking experiments revealed that corotoxigenin 3-O-glucopyranoside and calotropin interact with the cleft, so they were considered potential stabilizers of the p53-Y220C mutant comparable to the control drug 9H5, which was able to predict a position very similar to that already reported in the crystallographic structure. The ADME predicted that calotropin and desglucouzarin have more favorable pharmacokinetic parameters. Both molecules are predicted to be absorbed from the GIT. Conclusion: Calotropin of A. subulata is predicted to be a potential drug for p53-Y220C, because it binds to the cleft of the mutant and has favorable pharmacokinetic parameters. Corotoxigenin 3- O-glucopyranoside also binds to the Y220C cleft, but had less favorable pharmacokinetic parameters. These results have a future impact since calotropin could be used for the treatment of some types of cancer.
7
Bauer, Matthias R., Rhiannon N. Jones, Raysa K. Tareque, Bradley Springett, Felix A. Dingler, Lorena Verduci, Ketan J. Patel, Alan R. Fersht, Andreas C. Joerger, and John Spencer. "A structure-guided molecular chaperone approach for restoring the transcriptional activity of the p53 cancer mutant Y220C." Future Medicinal Chemistry 11, no. 19 (October 2019): 2491–504. http://dx.doi.org/10.4155/fmc-2019-0181.
Abstract:
Aim: The p53 cancer mutation Y220C creates a conformationally unstable protein with a unique elongated surface crevice that can be targeted by molecular chaperones. We report the structure-guided optimization of the carbazole-based stabilizer PK083. Materials & methods: Biophysical, cellular and x-ray crystallographic techniques have been employed to elucidate the mode of action of the carbazole scaffolds. Results: Targeting an unoccupied subsite of the surface crevice with heterocycle-substituted PK083 analogs resulted in a 70-fold affinity increase to single-digit micromolar levels, increased thermal stability and decreased rate of aggregation of the mutant protein. PK9318, one of the most potent binders, restored p53 signaling in the liver cancer cell line HUH-7 with homozygous Y220C mutation. Conclusion: The p53-Y220C mutant is an excellent paradigm for the development of mutant p53 rescue drugs via protein stabilization. Similar rescue strategies may be applicable to other cavity-creating p53 cancer mutations.
8
Baud, Matthias G. J., Matthias R. Bauer, Lorena Verduci, Felix A. Dingler, Ketan J. Patel, Deeptee Horil Roy, Andreas C. Joerger, and Alan R. Fersht. "Aminobenzothiazole derivatives stabilize the thermolabile p53 cancer mutant Y220C and show anticancer activity in p53-Y220C cell lines." European Journal of Medicinal Chemistry 152 (May 2018): 101–14. http://dx.doi.org/10.1016/j.ejmech.2018.04.035.
9
Schram, Alison M., Geoffrey I. Shapiro, Melissa L. Johnson, Anthony W. Tolcher, John A. Thompson, Anthony B. El-Khoueiry, Andrae L. Vandross, et al. "Abstract LB_A25: Updated Phase 1 results from the PYNNACLE Phase 1/2 study of PC14586, a selective p53 reactivator, in patients with advanced solid tumors harboring a TP53 Y220C mutation." Molecular Cancer Therapeutics 22, no. 12_Supplement (December 1, 2023): LB_A25. http://dx.doi.org/10.1158/1535-7163.targ-23-lb_a25.
Abstract:
Abstract Background: Mutations in the TP53 gene leading to p53 inactivation are the most common mutational event across human cancers. PC14586 is a first-in-class p53 reactivator that selectively binds to the mutated p53 Y220C protein and restores p53 wild-type activity. Preclinical data support potential for activity of PC14586 across TP53 Y220C-bearing tumors, with enhanced activity in KRAS wild-type (WT) models, consistent with the important parallel roles for p53 inactivation and oncogenic KRAS in tumorigenesis. Preliminary analysis of Phase 1 data from the Phase 1/2 PYNNACLE trial (NCT04585750) evaluating PC14586 in patients with advanced TP53 Y220C solid tumors showed that PC14586 was well tolerated with preliminary clinical activity across multiple tumor types in the efficacious dose range (1150 mg QD to 1500 mg BID). This updated Phase 1 analysis assesses PC14586 in patients treated across the efficacious dose range. Methods: Eligible patients (≥12 years) with locally advanced or metastatic solid tumors with a TP53 Y220C mutation received increasing oral doses of PC14586 to evaluate safety, PK, and preliminary efficacy via RECIST v1.1, and to determine the Recommended Phase 2 Dose (RP2D). Tumor molecular profiling was assessed for the impact of KRAS status on response. Results: As of 1 May 2023, 61 patients were treated in the efficacious dose range (safety population): median age 63 (range 32-84) years, 62% female, and median of 3 (range 1–9) prior lines of systemic therapy. The most frequent treatment-related adverse events (TRAEs) (≥10%) were nausea (42.3%), vomiting (35.2%), diarrhea (19.7%), increased creatinine (18.3%), fatigue (14.1%), and increased AST and ALT (12.7% each); 3% of patients discontinued PC14586 due to TRAEs. Most TRAEs were grade 1 or 2; the most common grade 3 TRAEs were anemia (4.2%) and increased ALT (2.8%). PC14586 administered with food led to improvement in nausea and vomiting. Dose proportional and linear PK was observed with a median half-life of 19 hours. Among patients with measurable disease, 36 patients had KRAS WT and 15 patients had KRAS mutated tumors. A total of 12 PRs (ORR 33.3%) were observed (9 confirmed and 3 unconfirmed - pending confirmation) in patients with KRAS WT disease across multiple tumor types including ovarian, breast, prostate, small-cell lung, and endometrial cancer. The median duration of confirmed response was 7 months. In patients with a KRAS mutation, there were no confirmed responses, although clinical activity was observed. At 2000 mg QD, the ORR was 46.2% in patients with TP53 Y220C and KRAS WT tumors (n=13). A RP2D of 2000 mg QD was selected based on overall safety, PK and preliminary efficacy. Conclusions: PC14586 was well-tolerated with a favorable safety profile. Efficacy was achieved in heavily pre-treated patients across multiple tumor types. The PYNNACLE registrational Phase 2 trial will assess PC14586 as monotherapy at the RP2D of 2000 mg QD in patients with TP53 Y220C and KRAS WT advanced solid tumors. Additional/updated data will be presented at the conference. Citation Format: Alison M Schram, Geoffrey I Shapiro, Melissa L Johnson, Anthony W. Tolcher, John A Thompson, Anthony B El-Khoueiry, Andrae L Vandross, Shivaani Kummar, Aparna R Parikh, Dale R Shepard, Ursula Garczarek, Kim LeDuke, Lisa Sheehan, Marc Fellous, Leila Alland, Ecaterina E Dumbrava. Updated Phase 1 results from the PYNNACLE Phase 1/2 study of PC14586, a selective p53 reactivator, in patients with advanced solid tumors harboring a TP53 Y220C mutation [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 LB_A25.
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Lane, David P., and Chandra S. Verma. "Covalent Rescue of Mutant p53." Cancer Discovery 13, no. 1 (January 9, 2023): 14–16. http://dx.doi.org/10.1158/2159-8290.cd-22-1212.
Abstract:
Summary: p53 mutant proteins are widely expressed in human cancer. In this issue, Guiley and Shokat describe the development of compounds that rescue the function of the Y220C mutant p53 protein by forming covalent complexes with the target protein. See related article by Guiley and Shokat, p. 56 (3).
Dissertations / Theses on the topic "Y220C":
1
Jones, Rhiannon N. "Towards the design and synthesis of a p53 mutant Y220C rescue drug." Thesis, University of Sussex, 2018. http://sro.sussex.ac.uk/id/eprint/74884/.
Abstract:
The DNA damage response is an important barrier to tumorigenesis. Impairment of p53 function is crucial to tumorigenesis by allowing evasion of p53 dependent responses. The mechanisms involve either (i) missense mutations, (ii) partial abrogation of signaling pathways or effector molecules that regulate p53, (iii) epigenetic deregulation. The tyrosine to cysteine mutation, Y220C, in p53 is found in around 100,000 new cancer cases per annum. This mutation destabilizes the core domain by 4 kcal mol-1 and destabilizes p53 under physiological conditions. The large to small mutation results in the fusing of two shallow pockets to create an extended surface cleft that a number of different fragments bind. The small molecule PK083, 1-(-ethyl-9H-carbazol-3-yl)-N-methanamine, binds the mutant-specific crevice with a KD = 150 μM and raised the protein mutant's half-life to over 15 minutes vs. 4 minutes in the absence of the ligand. This presents an ideal starting point towards the design of a p53 rescuing drug. A library of carbazoles was designed and synthesized, guided by SAR studies, crystallographic information and computational chemistry, with the aim of optimizing the structure toward a more potent PK083 analogue. Affinity gains were achieved by exploitation of direct fluorine-protein interactions between PK9255 (N-methyl-1-(9- (2,2,2-trifluoroethyl)-9H-carbazol-3-yl)methanamine), and the backbone carbonyls of Leu145 and Trp146 and the thiol of Cys220, resulting in a Kd = 28 μM. Further affinity gains were achieved through SAR studies targeting the proline-rich subsite II. Chemistry was optimized to allow a diversity-oriented synthesis toward 2,6,9- substituted carbazoles. A small library of PK083 analogues, where the subsite II targeting group was a halogen, ether, ester, amide or heterocycle were synthesized, identifying the heterocyclic compounds as most potent. A scan of heterocyclic compounds was carried out to identify the most potent heterocyclic substitution.
2
Eldawra, Eliana. "Effets tératogénique et oncogénique de la mutation Trp53 Y217C." Electronic Thesis or Diss., Sorbonne université, 2024. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2024SORUS072.pdf.
Abstract:
Le gène TP53 occupe la première place parmi les gènes fréquemment mutés dans les cancers humains. Il est responsable de la production du facteur de transcription p53, également appelée “gardien du génome”, avec des fonctions cellulaires diverses et des régulations complexes, largement reconnu aujourd'hui pour son rôle dans la suppression tumorale. Ma thèse s'est concentrée sur l’étude et la caractérisation de la mutation p53Y217C chez la souris (correspondant à p53Y220C chez l’homme). La plupart des mutations de TP53 affectent le domaine de liaison à l'ADN de la protéine et se trouvent généralement au niveau de sept “hotspot” mutationnels. Parmi celles-ci, la mutation Y220C est particulièrement intéressante, étant présente dans 100 000 nouveaux cas de cancer par an et dans 15 familles Li-Fraumeni prédisposées au cancer. Pour étudier cette mutation in vivo, on a développé un modèle murin exprimant une protéine p53 avec la mutation Y217C, équivalente à la Y220C chez l'homme. La caractérisation phénotypique de cette souris a révélé que la mutation non seulement désactive la fonction de la protéine, mais semble également conférer de nouvelles fonctions tératogénique et oncogéniqueThe TP53 gene is the most frequently mutated gene in human cancers. It is responsible for the production of the transcription factor p53, also known as the 'guardian of the genome', with diverse cellular functions and complex regulations, widely recognized today for its role in tumor suppression. My thesis focused on the study and characterization of the p53Y217C mutation in mice (corresponding to p53Y220C in humans). Most TP53 mutations affect the DNA-binding domain of the protein and are generally found at seven mutational hotspots. Of these, the Y220C mutation is of particular interest, being present in 100,000 new cases of cancer per year and in 15 cancer-prone Li-Fraumeni families. To study this mutation in vivo, we developed a mouse model expressing a p53 protein with the Y217C mutation, equivalent to Y220C in humans. Phenotypic characterization of this mouse revealed that the mutation not only deactivates the function of the protein, but also appears to confer new teratogenic and oncogenic functions
Books on the topic "Y220C":
1
Books, Bchimak. Libro de Contabilidad Ingresos y Gastos: Libro de Cuentas Simple y Fácil de Usar para Autónomos y Cuentas Profesionales, Cuaderno de Ingresos y Gastos Simple. Y220. Independently Published, 2021.
Conference papers on the topic "Y220C":
1
Dumble, Melissa, Lizhong Xu, Romyr Dominique, Binbin Liu, Hong Yang, Mary-Kate McBrayer, Dafydd Thomas, et al. "Abstract LB006: PC14586: The first orally bioavailable small molecule reactivator of Y220C mutant p53 in clinical development." In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-lb006.
2
Arowosafe, Toyin, Lucky Ishomo, Anthony Ogbebor, Esigie Benson, and Rita Aigbefo. "Thru Tubing Gaslift Installation Techniques in Dual Completion for Production Optimization and Improved Recovery in Brown Field Reservoirs." In SPE Nigeria Annual International Conference and Exhibition. SPE, 2023. http://dx.doi.org/10.2118/217476-ms.
Abstract:
Abstract There are several non-rig well intervention methods used in the oil industry to resuscitate dead wells back to production. One of such methods implemented for non-gaslift wells (or previously gas lifted wells with shallow mandrel depths) is the installation of Thru Tubing Gas Lift (TTGL) equipment at a pre-determined depth on the walls of the tubing. Most TTGL assemblies are usually fitted with one orifice valve to provide single-point injection. As a result of the single-point injection, well performance might be impacted overtime as reservoir pressure depletes and produced fluid composition changes. In such cases, deepening of injection point is required to restore the wells to production and ensure maximum oil recovery. However, these TTGL installation techniques are especially delicate to implement in wells with dual completions due to the execution complexities introduce by the presence of the adjacent tubing string, existing or adjacent perforations and injection points in the tubing. Dual oil producers, Wells X19B and Y22C were completed with dual completions without gas lift equipment in ED and ET field offshore Nigeria respectively. Well X19BL had TTGL installed about 8 years after it began production but, started to cycle gas through the TTGL point and was shut-in to curtail unwanted gas production to the surface facility. Well Y22CL and Wells Y22CU quit production on natural flow due to low well head pressure that resulted from decline in reservoir pressure Rig based interventions was uneconomic owing to the fact the remaining reserves were marginal. This paper discusses the techniques, challenges and operational learnings from the first-time application of TTGL deepening and TTGL installation in both dual strings despite complexities from well architecture and previous TTGL installation