From bench to bedside: current development and emerging trend of KRAS-targeted therapy
文献类型：期刊论文
| 作者 | Chen, Yi1,4 ; Liu, Qiu-pei3,4; Xie, Hua1,2,4; Ding, Jian1,4
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2023-12-04 |
| 页码 | 18 |
| ISSN号 | 1671-4083 |
| 关键词 | KRAS mutation KRAS(G12C) inhibitor Pan-KRAS inhibitor SHP2 allosteric inhibitor SOS1 inhibitor combination therapy |
| DOI | 10.1038/s41401-023-01194-4 |
| 通讯作者 | Xie, Hua(hxie@simm.ac.cn) ; Ding, Jian(jding@simm.ac.cn) |
| 英文摘要 | 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. |
| WOS关键词 | ALLOSTERIC SHP2 INHIBITOR ; TRI-COMPLEX INHIBITORS ; KRAS(G12C) INHIBITOR ; ANTITUMOR-ACTIVITY ; SMALL MOLECULES ; SOLID TUMORS ; AMG 510 ; K-RAS ; NUCLEOTIDE EXCHANGE ; PRECLINICAL MODELS |
| 资助项目 | National Natural Science Foundation of China[82273948] ; High-level Innovative Research Institute[2021B0909050003] ; State Key Laboratory of Drug Research[SKLDR-2023-TT-01] ; State Key Laboratory of Drug Research[SIMM2205KF-09] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | NATURE PUBL GROUP |
| WOS记录号 | WOS:001113601500001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/308131]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Xie, Hua; Ding, Jian |
| 作者单位 | 1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 2.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China 3.Univ Nottingham Ningbo China, Dept Chem & Environm Engn, Sci & Engn Bldg, Ningbo 315100, Peoples R China 4.Chinese Acad Sci, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Yi,Liu, Qiu-pei,Xie, Hua,et al. From bench to bedside: current development and emerging trend of KRAS-targeted therapy[J]. ACTA PHARMACOLOGICA SINICA,2023:18. |
| APA | Chen, Yi,Liu, Qiu-pei,Xie, Hua,&Ding, Jian.(2023).From bench to bedside: current development and emerging trend of KRAS-targeted therapy.ACTA PHARMACOLOGICA SINICA,18. |
| MLA | Chen, Yi,et al."From bench to bedside: current development and emerging trend of KRAS-targeted therapy".ACTA PHARMACOLOGICA SINICA (2023):18. |
入库方式： OAI收割
来源：上海药物研究所
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