摘要
KRAS(Kirsten-RAS)是RAS(rat sarcoma)基因家族常见的突变基因之一,负责细胞生长、分化、增殖和生存信号通路的调控。KRAS突变后,其蛋白持续活化,异常激活下游信号通路,导致不受控制的细胞生长和肿瘤的产生。然而,市场上还没有直接针对KRAS并抑制其异常功能的药物,KRAS一度被认为不可成药靶标。随着KRAS^(G12C)突变变构调节剂的发现和Sotorasib(研发代号:AMG510)的上市及其在临床上取得的突出应用效果终于打破了这一瓶颈,目前有大量的KRAS^(G12C)突变变构调节剂、pan-KRAS抑制剂和KRAS(ON)抑制剂相继被发现并有多个药物处于临床研究阶段。此外,靶向降解KRAS^(G12C)的蛋白降解靶向嵌合体(PROTAC)类药物研发也取得了突破进展,其独特的作用机制将开创KRAS药物研发的新方向,KRAS抑制剂临床应用中的耐药问题有望得到解决。本文对KRAS及其抑制剂的研发进展、临床应用情况、近年来KRAS抑制剂研究所面临的挑战及解决策略进行综述,并对未来KRAS抑制剂的发展前景进行展望。
KRAS(Kirsten-RAS)is one of the common mutated genes in RAS(rat sarcoma)gene family that acts as important switch in intracellular signaling pathways and plays a key role in regulation of cell proliferation,differentiation and survival.When KRAS is mutated,KRAS protein is continuously activated,which leads to the activation of multiple downstream signaling pathways and induces the occurrence and development of malignant tumors.However,the development of targeted drugs against KRAS gene mutations has failed,and KRAS was once considered to be an undruggable target.With the discovery of KRAS^(G12C) mutant and the marketing of Sotorasib and its outstanding clinical application,this bottleneck has finally been broken.At present,a number of KRAS^(G12C) mutation-allosteric modulators,pan-KRAS inhibitors and KRAS(ON)inhibitors have been discovered and several drugs are under clinical study.In addition,a breakthrough has been made in the development of proteolysis-targeting chimeras(PROTAC)drugs targeting KRAS^(G12C) degradation.Its unique mechanism of action will create a new direction for KRAS drug development and is expected to solve the problem of drug resistance in the clinical application of KRAS inhibitors.Herein,we reviewed the research and development progress and clinical application of KRAS and its inhibitors,as well as the challenges and solutions of KRAS inhibitor research in recent years,and the development prospects of KRAS inhibitors in the future.
作者
杨宁
李鹏运
郑志兵
YANG Ning;LI Peng-yun;ZHENG Zhi-bing(National Engineering and Technology Center of Emergency Prevention and Control Drugs,Institute of Pharmacology&Toxicology of AMMS,Beijing 100850,China)
出处
《临床药物治疗杂志》
2022年第3期13-21,共9页
Clinical Medication Journal
作者简介
通信作者:郑志兵,博士研究生,研究员,研究方向:新药合成与设计。E-mail:zzbcaptain@aliyun.com。
