靶向 p53 的小分子矫正剂和稳定剂。
Small-molecule correctors and stabilizers to target p53.
机构信息
Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA; Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA 92697, USA.
Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA 92697, USA; Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, Irvine, CA 92697, USA.
出版信息
Trends Pharmacol Sci. 2023 May;44(5):274-289. doi: 10.1016/j.tips.2023.02.007. Epub 2023 Mar 22.
The tumor suppressor p53 is the most frequently mutated protein in human cancer and tops the list of high-value precision oncology targets. p53 prevents initiation and progression of cancer by inducing cell-cycle arrest and various forms of cell death. Tumors have thus evolved ways to inactivate p53, mainly by TP53 mutations or by hyperactive p53 degradation. This review focuses on two types of p53 targeting compounds, MDM2 antagonists and mutant p53 correctors. MDM2 inhibitors prevent p53 protein degradation, while correctors restore tumor suppressor activity of p53 mutants by enhancing thermodynamic stability. Herein we explore both novel and repurposed p53 targeting compounds, discuss their mode of action, and examine the challenges in advancing them to the clinic.
抑癌基因 p53 是人类癌症中最常发生突变的蛋白，也是高价值精准肿瘤学靶标的首选。p53 通过诱导细胞周期停滞和各种形式的细胞死亡来防止癌症的发生和进展。肿瘤因此进化出了使 p53 失活的方法，主要通过 TP53 突变或过度活跃的 p53 降解。本综述重点介绍了两种靶向 p53 的化合物，MDM2 拮抗剂和突变型 p53 矫正剂。MDM2 抑制剂阻止 p53 蛋白降解，而矫正剂通过增强热力学稳定性来恢复 p53 突变体的肿瘤抑制活性。本文探讨了新型和再利用的 p53 靶向化合物，讨论了它们的作用机制，并研究了将它们推向临床应用所面临的挑战。
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