Discovery of Rezatapopt (PC14586), a First-in-Class, Small-Molecule Reactivator of p53 Y220C Mutant in Development.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-11-04 eCollection Date: 2025-01-09 DOI:10.1021/acsmedchemlett.4c00379

Binh T Vu, Romyr Dominique, Bruce J Fahr, Hongju H Li, David C Fry, Lizhong Xu, Hong Yang, Anna Puzio-Kuter, Andrew Good, Binbin Liu, Kuo-Sen Huang, Naoko Tanaka, Thomas W Davis, Melissa L Dumble

{"title":"Discovery of Rezatapopt (PC14586), a First-in-Class, Small-Molecule Reactivator of p53 Y220C Mutant in Development.","authors":"Binh T Vu, Romyr Dominique, Bruce J Fahr, Hongju H Li, David C Fry, Lizhong Xu, Hong Yang, Anna Puzio-Kuter, Andrew Good, Binbin Liu, Kuo-Sen Huang, Naoko Tanaka, Thomas W Davis, Melissa L Dumble","doi":"10.1021/acsmedchemlett.4c00379","DOIUrl":null,"url":null,"abstract":"p53 is a potent transcription factor that is crucial in regulating cellular responses to stress. Mutations in the TP53 gene are found in >50% of human cancers, predominantly occurring in the DNA-binding domain (amino acids 94-292). The Y220C mutation accounts for 1.8% of all of the TP53 mutations and produces a thermally unstable protein. Rezatapopt (also known as PC14586) is the first small-molecule p53 Y220C reactivator being evaluated in clinical trials. Rezatapopt was specifically designed to tightly bind to a pocket created by the TP53 Y220C mutation. By stabilization of the p53 protein structure, rezatapopt restores p53 tumor suppressor functions. In mouse models with established human tumor xenografts harboring the TP53 Y220C mutation, rezatapopt demonstrated tumor inhibition and regression at well-tolerated doses. In Phase 1 clinical trials, rezatapopt demonstrated a favorable safety profile within the efficacious dose range and showed single-agent efficacy in heavily pretreated patients with various TP53 Y220C mutant solid tumors.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 1","pages":"34-39"},"PeriodicalIF":3.5000,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11726359/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acsmedchemlett.4c00379","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/9 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

p53 is a potent transcription factor that is crucial in regulating cellular responses to stress. Mutations in the TP53 gene are found in >50% of human cancers, predominantly occurring in the DNA-binding domain (amino acids 94-292). The Y220C mutation accounts for 1.8% of all of the TP53 mutations and produces a thermally unstable protein. Rezatapopt (also known as PC14586) is the first small-molecule p53 Y220C reactivator being evaluated in clinical trials. Rezatapopt was specifically designed to tightly bind to a pocket created by the TP53 Y220C mutation. By stabilization of the p53 protein structure, rezatapopt restores p53 tumor suppressor functions. In mouse models with established human tumor xenografts harboring the TP53 Y220C mutation, rezatapopt demonstrated tumor inhibition and regression at well-tolerated doses. In Phase 1 clinical trials, rezatapopt demonstrated a favorable safety profile within the efficacious dose range and showed single-agent efficacy in heavily pretreated patients with various TP53 Y220C mutant solid tumors.

查看原文本刊更多论文

发现 Rezatapopt (PC14586)，它是开发中 p53 Y220C 突变体的第一类小分子活化剂。

P53是一种有效的转录因子，在调节细胞应激反应中起着至关重要的作用。在50%的人类癌症中发现TP53基因突变，主要发生在dna结合区域（氨基酸94-292）。Y220C突变占所有TP53突变的1.8%，并产生一种热不稳定的蛋白质。Rezatapopt（也被称为PC14586）是第一个正在临床试验中评估的小分子p53 Y220C再激活剂。Rezatapopt是专门设计与TP53 Y220C突变产生的口袋紧密结合的。通过稳定p53蛋白结构，rezatapopt恢复p53肿瘤抑制功能。在携带TP53 Y220C突变的人类肿瘤异种移植物的小鼠模型中，rezatapopt在耐受良好的剂量下显示出肿瘤抑制和消退。在1期临床试验中，rezatapopt在有效剂量范围内显示出良好的安全性，并在各种TP53 Y220C突变体实体瘤的重度预处理患者中显示出单药疗效。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.