Development of small-molecule tropomyosin receptor kinase(TRK)inhibitors for NTRK fusion cancers

• 作者: Tingting Jiang Guan Wang Yao Liu Lu Feng Meng Wang Jie Liu Yi Chen Liang Ouyang
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（2）
• 所属期刊栏目: Reviews
• 页码范围: 355-372
• 页数: 18页
• 语种: 英文

摘要

Tropomyosin receptor kinase A,B and C(TRKA,TRKB and TRKC),which are well-known members of the cell surface receptor tyrosine kinase(RTK)family,are encoded by the neurotrophic re-ceptor tyrosine kinase 1,2 and 3(NTRK1,NTRK2 and NTRK3)genes,respectively.TRKs can regulate cell proliferation,differentiation and even apoptosis through the RAS/MAPKs,PI3K/AKT and PLCy pathways.Gene fusions involving NTRK act as oncogenic drivers of a broad diversity of adult and pedi-atric tumors,and TRKs have become promising antitumor targets.Therefore,achieving a comprehensive understanding of TRKs and relevant TRK inhibitors should be urgently pursued for the further develop-ment of novel TRK inhibitors for potential clinical applications.This review focuses on summarizing the biological functions of TRKs and NTRK fusion proteins,the development of small-molecule TRK inhib-itors with different chemotypes and their activity and selectivity,and the potential therapeutic applica-tions of these inhibitors for future cancer drug discovery efforts.