靶向Ras蛋白的抗癌药物  

Anticancer drugs targeting Ras protein

作　　者：杜禹 冯强 杨举伦 DU Yuu;FENG Qiang;YANG Julun(Clinical College of the 920th Hospital of Kunming Medical University,Kunming 650032,China;department of Pathology,920th Hospital of the Joint Logistics Support Force of PLA,Kunming 650032,China)

机构地区：[1]昆明医科大学第九二〇医院临床学院,昆明650032 [2]联勤保障部队第九二〇医院病理科,昆明650032

出　　处：《生命的化学》2021年第10期2134-2139,共6页Chemistry of Life

基　　金：云南省科技计划重大专项(2018ZF009)。

摘　　要：Ras蛋白是Ras信号通路调控的关键分子,与30%人类肿瘤的发生和进展密切相关,研发针对Ras蛋白的抗癌药物具有重要意义。经过数十年的努力,过去因技术限制和对Ras性质及结构认识不足导致的Ras靶向药物研发缓慢的局面如今已有新突破。目前已有多种抗Ras蛋白的单克隆抗体和单链抗体问世。Ras蛋白的这些抗体通过与Ras蛋白特异结合使其失去调控Ras信号通路的作用,目前正在解决这些抗体穿透肿瘤细胞膜进入细胞的难题。已合成多种Ras蛋白抑制剂,如化合物SML-10701、3144、DCAI、AMG 510、MRTX 849和Cyclorasin等,其中AMG 510已进行Ⅲ期临床试验,其他的抑制剂在细胞膜穿透能力和肿瘤抑制效果方面有较大改善。Ras翻译后修饰抑制剂GGTI-2418、NSC1011和Cysmethynil等通过影响Ras蛋白的细胞内定位而阻断Ras信号通路,提高这类抑制剂抑制效果的研究仍在继续。本文从抗Ras蛋白抗体、Ras蛋白抑制剂和Ras翻译后修饰抑制剂三个方面综述近些年Ras蛋白靶向药物的研究进展,为ras基因驱动肿瘤的治疗提供参考。Ras protein is a key molecule in regulation of Ras signaling pathway,which is closely related to development and progression in 30%of human tumors.It is of great significance to develop anti-cancer drugs for Ras protein.After decades of unremitting efforts,there has been a new breakthrough in the slow development of Ras targeted drugs due to technical limitations and insufficient understanding of the nature and structure of Ras.A variety of monoclonal antibodies and single chain variable fragment antibody against Ras protein have been reported.These antibodies could block Ras signaling pathway by binding with Ras protein.Many kinds of Ras protein inhibitors have been synthesized,such as SML-10701,3144,DCAI,AMG 510,MRTX 849 and Cyclorasin.Among them,AMG 510 has been approved by FDA for clinical application.Other inhibitors made great progress in improving the ability to penetrate cell membrane and enhancing the inhibitory effect.Ras post-translational modification inhibitors,for instance,compounds GGTI-2418,NSC1011 and Cysmethynil,could also block Ras signaling pathway.The research on improving the inhibitory effect of these inhibitors is still continuing.This work reviews the recent progress of Ras protein targeted drugs from three aspects:anti-Ras protein antibodies,Ras-binding direct inhibitors and Ras post-translational modification inhibitors,so as to provide reference for the treatment of ras gene driven tumors.

关 键 词：RAS蛋白 抗癌药物 靶向治疗 抗体 抑制剂 

分 类 号：R979.1[医药卫生—药品]