From bench to bedside: current development and emerging trend of KRAS-targeted therapy  

作　　者：Yi Chen Qiu-pei Liu Hua Xie Jian Ding 

机构地区：[1]Division of Antitumor Pharmacology,State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,201203,China [2]University of Chinese Academy of Sciences,Beijing,100049,China [3]Department of Chemical and Environment Engineering,Science and Engineering Building,The University of Nottingham Ningbo China,Ningbo,315100,China [4]Zhongshan Institute for Drug Discovery,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Zhongshan,528400,China

出　　处：《Acta Pharmacologica Sinica》2024年第4期686-703,共18页中国药理学报（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China(82273948);High-level Innovative Research Institute(2021B0909050003);State Key Laboratory of Drug Research(SKLDR-2023-TT-01 and SIMM2205KF-09).

摘　　要：Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) is the most frequently mutated oncogene in human cancers with mutations predominantly occurring in codon 12. These mutations disrupt the normal function of KRAS by interfering with GTP hydrolysis and nucleotide exchange activity, making it prone to the GTP-bound active state, thus leading to sustained activation of downstream pathways. Despite decades of research, there has been no progress in the KRAS drug discovery until the groundbreaking discovery of covalently targeting the KRAS^(G12C) mutation in 2013, which led to revolutionary changes in KRAS-targeted therapy. So far, two small molecule inhibitors sotorasib and adagrasib targeting KRAS^(G12C) have received accelerated approval for the treatment of non-small cell lung cancer (NSCLC) harboring KRAS^(G12C) mutations. In recent years, rapid progress has been achieved in the KRAS-targeted therapy field, especially the exploration of KRAS^(G12C) covalent inhibitors in other KRAS^(G12C)-positive malignancies, novel KRAS inhibitors beyond KRAS^(G12C) mutation or pan-KRAS inhibitors, and approaches to indirectly targeting KRAS. In this review, we provide a comprehensive overview of the molecular and mutational characteristics of KRAS and summarize the development and current status of covalent inhibitors targeting the KRAS^(G12C) mutation. We also discuss emerging promising KRAS-targeted therapeutic strategies, with a focus on mutation-specific and direct pan-KRAS inhibitors and indirect KRAS inhibitors through targeting the RAS activation-associated proteins Src homology-2 domain-containing phosphatase 2 (SHP2) and son of sevenless homolog 1 (SOS1), and shed light on current challenges and opportunities for drug discovery in this field.

关 键 词：KRAS mutation KRAS^(G12C)inhibitor Pan-KRAS inhibitor SHP2 allosteric inhibitor SOS1 inhibitor combination therapy 

分 类 号：R730.5[医药卫生—肿瘤]