靶向KRAS蛋白抑制剂的研究进展  

Research progress of KRAS inhibitors

作　　者：李学燕 陈娜 江程[1] LI Xueyan;CHEN Na;JIANG Cheng(School of Pharmacy,China Pharmaceutical University,Nanjing 211198,China)

机构地区：[1]中国药科大学药学院,南京211198

出　　处：《中国药科大学学报》2024年第2期257-269,共13页Journal of China Pharmaceutical University

摘　　要：KRAS蛋白是由克里斯汀鼠肉瘤病毒基因(Kirsten rat sarcoma viral oncogene,KRAS)编码的一种小GTP酶,参与细胞的增殖、分化、迁移和凋亡等活动,被认为是调控细胞生命周期的信号开关。然而KRAS基因容易发生突变导致下游信号通路的过度激活,是肿瘤疾病发生发展的重要因素。KRAS蛋白常见突变位点包括G12、G13和Q61,不同的突变体对蛋白生理功能的影响和主要肿瘤疾病类型具有差异性。KRAS蛋白由于其光滑的表面和对核苷酸的高亲和力一度被认为是“不可成药”的靶点。直到靶向KRAS G12C共价抑制剂索托雷塞(sotorasib)和阿达格拉西布(adagrasib)的上市才打破了KRAS不可成药的现状。文章就KRAS蛋白的结构和功能以及直接靶向KRAS G12C、KRAS G12D、KRAS G12R、KRAS G12S和泛KRAS抑制剂的研究现状、面临的挑战进行综述,旨在为KRAS抑制剂的发展提供有益参考。KRAS protein,a small GTPase encoded by the Kirsten rat sarcoma viral oncogene homologue(KRAS)gene,is involved in cell proliferation,differentiation,migration and cell survival,and is known as a regulatory switch for the cell life cycle.However,KRAS gene is prone to mutation,leading to hyperactivation of its downstream signaling pathways,and has a vital role in driving tumorigenesis.KRAS mutations predominantly take place at residue G12,G13 or Q61,and different mutants have varying effects on protein physiological functions and tumor types.Due to its smooth surface and high affinity for nucleotides,KRAS had been considered to be“undruggable”until the launch of selective KRAS G12C inhibitors sotorasib and adagrasib,which broke the dogma.This review introduces the structure and functions of KRAS,as well as the status and progress of inhibitors directly targeting KRAS mutants(G12C,G12D,G12R,G12S)and pan-KRAS inhibitors,aiming to provide some insightful reference for the development of KRAS inhibitors.

关 键 词：RAS KRAS KRAS抑制剂 抗肿瘤 

分 类 号：R914[医药卫生—药物化学]