药学学报, 2021, 56(2): 374-382
引用本文:
李歆, 王义俊, 刘平羽. 特异靶向KRAS-G12C突变的抗肿瘤药物研究进展[J]. 药学学报, 2021, 56(2): 374-382.
LI Xin, WANG Yi-jun, LIU Ping-yu. Recent advancement in targeting the KRAS-G12C mutant for cancer therapy[J]. Acta Pharmaceutica Sinica, 2021, 56(2): 374-382.

特异靶向KRAS-G12C突变的抗肿瘤药物研究进展
李歆1, 王义俊2, 刘平羽2
1. 南京医科大学药学院, 江苏 南京 211166;
2. 南京医科大学第二附属医院药学部, 江苏 南京 210011
摘要:
RAS是肿瘤中突变最为广泛的癌基因,但是至今尚无针对RAS突变肿瘤的靶向治疗药物获批在临床使用。近年来,针对KRAS-G12C突变体的抑制剂研发进展迅猛,被认为是当前针对RAS突变肿瘤最具希望的突破方向。本综述围绕KRAS-G12C突变,重点介绍了针对半胱氨酸的共价抑制剂研发进展、联合用药策略和基于蛋白降解的蛋白水解靶向嵌合体(PROTACs)技术的应用,总结了相关新药研发的最新进展。自2013年首个针对KRAS-G12C的共价抑制剂被报道以来,该领域已经取得了快速进展,目前进展较快的化合物已在临床取得显著疗效,极有希望在近期上市;PROTACs降解剂的研发虽然刚刚起步,新近也获得了显著进展,有望带来新的希望。针对RAS的抗肿瘤药物研发有望迎来首个突破,但也仍面临着诸多挑战,进一步优化技术、探明机制和明晰策略将是未来的努力方向。
关键词:    KRAS突变肿瘤      KRAS-G12C突变体      抗肿瘤药物      共价抑制剂      蛋白水解靶向嵌合体      联合用药     
Recent advancement in targeting the KRAS-G12C mutant for cancer therapy
LI Xin1, WANG Yi-jun2, LIU Ping-yu2
1. School of Pharmacy, Nanjing Medical University, Nanjing 211166, China;
2. Pharmacy Department, the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China
Abstract:
RAS, as a well-known proto-oncogene, is the most frequently mutated oncogene in human cancers, yet tremendous efforts over the past 30 years have failed to develop effective therapies for RAS-mutant cancer. Recently, specifically targeting the KRAS-G12C mutant, a frequently occurring KRAS mutation in human cancers, has shown promise in conquering KRAS-mutant cancers, and has inspired interest in this direction. We herein review the very recent progress achieved in the development of covalent inhibitors towards KRAS-G12C mutant, in combinational therapies and in proteolysis-targeting chimeras (PROTACs)-based approaches to disrupt KRAS-G12C protein. We provide insights for drug discovery against KRAS-G12C-mutated tumors and discuss the potential challenges in this field.
Key words:    KRAS mutated cancer    KRAS-G12C mutant    anticancer drug    covalent inhibitor    proteolysis-targeting chimeras    combination therapy   
收稿日期: 2020-09-14
DOI: 10.16438/j.0513-4870.2020-1485
基金项目: 国家自然科学基金资助项目(72074123).
通讯作者: 刘平羽,Tel:86-25-58509955,E-mail:20953836@qq.com
Email: 20953836@qq.com
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