有机化学 ›› 2022, Vol. 42 ›› Issue (7): 2055-2069.DOI: 10.6023/cjoc202112020 上一篇    下一篇

综述与进展

原肌球蛋白受体激酶(TRK)抑制剂的研究进展

杨竣喆a,b, 许子超b, 李淳朴b, 程远征a,*(), 柳红a,b,*()   

  1. a潍坊医学院药学院 山东潍坊 261053
    b中国科学院上海药物研究所 新药研究国家重点实验室 上海 201203
  • 收稿日期:2021-12-16 修回日期:2022-03-02 发布日期:2022-08-09
  • 通讯作者: 程远征, 柳红
  • 作者简介:
    共同第一作者
  • 基金资助:
    国家自然科学基金(81620108027); 国家自然科学基金(21632008); 国家自然科学基金(21907102); 国家重点研发计划(2020YFC0841400)

Research Progress of Tropomyosin Receptor Kinase (TRK) Inhibitors

Junzhe Yanga,b, Zichao Xub, Chunpu Lib, Yuanzheng Chenga(), Hong Liua,b()   

  1. aSchool of Pharmacy, Weifang Medical College, Weifang, Shangdong 261053
    bState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203
  • Received:2021-12-16 Revised:2022-03-02 Published:2022-08-09
  • Contact: Yuanzheng Cheng, Hong Liu
  • About author:
    These authors contributed equally to this work
  • Supported by:
    National Natural Science Foundation of China(81620108027); National Natural Science Foundation of China(21632008); National Natural Science Foundation of China(21907102); National Key Research and Development (R&D) Program of China(2020YFC0841400)

原肌球蛋白受体激酶(TRK)是一类由神经生长因子激活的酪氨酸激酶家族, 包括TRKA, TRKB和TRKC三个亚型, 分别由NTRK1 (neurotrophic receptor tyrosine kinase 1), NTRK2NTRK3基因编码. TRK激酶被磷酸化后, 能够激活下游信号分子, 进而调节细胞增殖、分化、代谢和凋亡等作用. NTRK基因可以与其他基因发生融合, 导致激酶的高表达或者激酶活性的持续升高, 诱发癌症. 靶向NTRK融合基因的主要策略是开发作用于胞内激酶区的TRK小分子抑制剂, 近年来TRK小分子抑制剂的开发也受到了研究人员的关注. 对TRK激酶的结构、生理功能、TRK抑制剂以及克服耐药的治疗策略等内容进行综述.

关键词: 原肌球蛋白受体激酶, 抗肿瘤, 抑制剂

Tropomyosin receptor kinase (TRK) is a tyrosine kinase family activated by nerve growth factor, including TRKA, TRKB and TRKC, which are encoded by NTRK1 (neurorosine receptor tyrosine kinase 1), NTRK2 and NTRK3 genes, respectively. After phosphorylation, TRK kinase can activate downstream signaling molecules, and then regulate cell proliferation, differentiation, metabolism and apoptosis. The NTRK gene can fuse with other genes, resulting in high kinase expression or continuous increase of kinase activity, leading to cancer. The main strategy for targeting NTRK fusion genes is to develop small molecule inhibitors of TRK that act on the intracellular kinase region. In recent years, the development of TRK small molecule inhibitors has also attracted the attention of researchers. The structure, physiological function, TRK inhibitors and therapeutic strategies to overcome drug resistance of TRK kinase are reviewed.

Key words: tropomyosin receptor kinase, anticancer, inhibitor