靶向突变p53蛋白的抗肿瘤药物

Antitumor Drugs Targeting Mutant p53 Protein

p53蛋白是人体内十分重要的肿瘤抑制因子,通过调节细胞周期阻滞、诱导细胞凋亡等作用发挥肿瘤抑制功能。突变后的p53蛋白不仅具有显性负性效应(dominant negative effect,DN)抑制野生型p53蛋白功能,而且还通过功能获得性效应(gain of function,GOF)调节细胞代谢、侵袭、迁移等方式促进肿瘤的发生。p53蛋白在超过50%的肿瘤组织中发生突变,是肿瘤细胞区别于正常细胞的一个特异性药物靶点。因此,针对突变p53蛋白开发新型抗癌药物一直是研究的热点。长期以来,由于突变p53蛋白表面较为光滑,缺乏药物结合口袋,使其被认为是一个不可成药的靶点。随着高通量筛选技术的发展以及对突变p53蛋白结构的深入了解,许多靶向突变p53蛋白的小分子化合物被报道并在体外展现出较好的抗肿瘤活性,多款基于突变p53蛋白研发的化合物已经进入临床试验阶段。本文就靶向p53蛋白治疗肿瘤的直接和间接策略进行综述,重点针对突变p53蛋白重激活剂与降解突变p53蛋白的小分子化合物作用机制进行梳理,以期为后续开发靶向突变p53蛋白药物的创新提供帮助。

The p53 protein is an essential tumor suppressor in the human body that plays a critical role in preventing tumor formation by controlling cell cycle arrest and promoting apoptosis.Mutations in the p53 gene are frequently observed in more than 50%of tumor tissues and lead to the generation of mutant p53 proteins,which not only have a dominant-negative effect(DN)that hinders the function of wild-type p53 protein but also have gain-of-function(GOF)effects that stimulate tumor development by regulating cell metabolism,invasion,migration,and other processes.Therefore,mutant p53 protein has become a specific drug target for cancer therapy.However,the lack of a drug-binding pocket and smooth surface of mutant p53 proteins have made them undruggable targets for a long time.In recent years,with the development of high-throughput screening technology and an enhanced understanding of the structure and conformational changes exhibited by mutant p53 proteins,a multitude of small molecule compounds directed against mutant p53 protein have been identified,exhibiting substantial in vitro anti-tumor efficacy.Moreover,some of these compounds have entered clinical trials.This review summarized the direct and indirect strategies for the treatment of cancers targeting mutant p53,with a primary focus on the mechanisms of action of small molecule compounds that reactivate mutant p53 protein or degrade mutant p53 protein.The aim is to provide assistance for the development of innovative drugs targeting mutant p53 protein in the future.