Puzio-Kuter Anna M, Xu Lizhong, McBrayer Mary Kate, Dominique Romyr, Li Hongju H, Fahr Bruce J, Brown Alyssa M, Wiebesiek Amy E, Russo Brandon M, Mulligan Chris L, Yang Hong, Battaglia Josh, Robell Kimberly A, Thomas Dafydd H, Huang Kuo-Sen, Solovyov Alexander, Greenbaum Benjamin D, Oliner Jonathan D, Davis Thomas W, Dumble Melissa L, Johnson Melissa L, Xiong Shunbin, Yang Peirong, Lozano Guillermina, Fellous Marc M, Vu Binh T, Schram Alison M, Levine Arnold J, Poyurovsky Masha V
PMV Pharmaceuticals, Inc, Princeton, New Jersey.
Cepter Biopartners, Nutley, New Jersey.
Cancer Discov. 2025 Jun 3;15(6):1159-1179. doi: 10.1158/2159-8290.CD-24-1421.
Restoration of the tumor suppressor function of tumor-associated p53 mutants, including the Y220C substitution, has posed a significant challenge for therapeutic discovery. In this study, we describe rezatapopt (PC14586), part of a series of compounds designed to reactivate the p53 Y220C mutant. These compounds restore p53 tumor suppressor function by correcting its conformation and enabling it to bind DNA and activate downstream target genes, thus inducing antiproliferative changes in tumor cells. Our findings are supported by biochemical and structural analysis, in vitro and in vivo transcriptomics, and functional data, revealing the recovery of multiple aspects of the wild-type p53 program. These compounds demonstrate potent antitumor activity in preclinical models as single agents and in combination with immunotherapy. Currently, rezatapopt is being evaluated in a registrational phase II clinical trial for patients with advanced solid tumors harboring the TP53 Y220C mutation.
Rezatapopt is a clinical-stage compound that offers a promising treatment option for TP53-mutant cancers. This study details the characterization of rezatapopt and its related compounds, which can reinstate the tumor suppressor activity of the p53 Y220C mutant. These results emphasize the potential for targeting p53 mutations in cancer therapy.
恢复肿瘤相关p53突变体（包括Y220C替换）的肿瘤抑制功能，对治疗方法的发现构成了重大挑战。在本研究中，我们描述了瑞扎凋亡素（PC14586），这是一系列旨在重新激活p53 Y220C突变体的化合物之一。这些化合物通过纠正其构象、使其能够结合DNA并激活下游靶基因，从而恢复p53肿瘤抑制功能，进而在肿瘤细胞中诱导抗增殖变化。我们的研究结果得到了生化和结构分析、体外和体内转录组学以及功能数据的支持，揭示了野生型p53程序多个方面的恢复。这些化合物在临床前模型中作为单一药物以及与免疫疗法联合使用时均显示出强大的抗肿瘤活性。目前，瑞扎凋亡素正在针对携带TP53 Y220C突变的晚期实体瘤患者进行注册II期临床试验评估。
瑞扎凋亡素是一种临床阶段的化合物，为TP53突变型癌症提供了一种有前景的治疗选择。本研究详细描述了瑞扎凋亡素及其相关化合物的特性，它们可以恢复p53 Y220C突变体的肿瘤抑制活性。这些结果强调了在癌症治疗中靶向p53突变的潜力。
