《生命科学》 2017, 29(6): 589-599

Trk激酶与肿瘤发生的关系及其小分子抑制剂的研究进展

王　田1，毛伟峰1，吴燕华2*

(1 上海药明康德新药开发有限公司生物部，上海 200131；2 复旦大学生命科学学院，上海 200438)

摘　要：摘　要：Trk 是一类神经生长因子激活的酪氨酸激酶家族，包括TrkA、TrkB 和TrkC 3 个亚型，分别由NTRK1 (neurotrophic receptor tyrosine kinase 1)、NTRK2 和NTRK3 基因编码。Trk 激酶被磷酸化后，能够激活下游信号分子，从而起到调节细胞增殖、分化、代谢、凋亡等作用。NTRK 基因可以与其他基因发生融合，导致Trk 激酶的高表达或者Trk 激酶活性持续升高，最终可能引起癌症的发生。近几年来，Trk 激酶的小分子抑制剂作为一种新的癌症治疗手段，进入人们的视线，这些化合物对NTRK 基因融合的癌症患者有显著的治疗效果。现总结了Trk 激酶的结构及生理功能，以及NTRK 基因融合与肿瘤发生的关系；同时列举了10多种近十几年来研究发现的Trk 激酶抑制剂，并讨论了其分子抑制的机制以及未来的发展方向。

Roles of tropomyosin-related kinases in tumorigenesis and their small molecular inhibitors

WANG Tian1， MAO Wei-Feng1， WU Yan-Hua2*

(1 Biology Department， WuXi AppTec， Shanghai 200131， China; 2 School of Life Science， Fudan University， Shanghai 200438， China)

Abstract: Abstract: Tropomyosin-related kinases (Trks) are a group of receptor tyrosine kinases which are regulated by neurotrophins， including 3 members TrkA， TrkB and TrkC， encoded by the genes NTRK1， NTRK2 and NTRK3 respectively. Many cellular functions， for example， cell proliferation， cell differentiation， metabolism and apoptosis are mediated by Trks through phosphorylation and regulation of their downstream substrates. Gene fusions involving NTRK genes result in continuous activation or overexpression of these kinases， which increase the risk of tumor genesis. Inhibition of Trks becomes a novel potential cancer therapy. A few of inhibitors have entered clinical trials in recent years and showed significant therapeutic effects in patients harboring NRTK gene fusions. In this article， we summarize the structures and biological functions of Trks， their relationship with NTRK gene fusions in tumorigenesis. Meanwhile， a couple of small molecular inhibitors against Trks and their molecular mechanism of inhibition are introduced.