Design, synthesis and biological activity of bicyclic carboxamide derivatives as TRK inhibitors

Abstract ‘precision medicine’ is characterized by the selection of targeted drugs based on genetic characteristics of tumor from patients, and no longer selected basis on the type of cancer tissue. Among them, clinical trials on neurotrophin receptor tyrosine kinase genes (NTRK) have proven that great anti-cancer effects can be achieved in different cancer patients. In this paper, a novel total of twenty compounds in two categories have been designed and synthesized. Results of Kinase activity tests showed that I-9 (TRKA IC50 = 1.3 nM, TRKAG595R IC50 = 6.1 nM), and I-10 (TRKA IC50 = 1.1 nM, TRKAG595R IC50 = 5.3 nM) have significant inhibitory activity, and results of cell viability tests showed that I-9 and I-10 can maintain a great inhibitory effect in the Ba/F3-LMNA-NTRK1 cell line(IC50 = 81.1 nM and 41.7 nM, respectively), and in Ba/F3-LMNA-NTRK1-G595R cell line, I-9 and I-10 have better cell activity (IC50 was 495.3 nM, 336.6 nM, respectively) compared with the positive control drug LOXO-101. These results indicate that I-9 and I-10 are potential TRK inhibitors that can overcome drug resistance for further investigation.