Design, synthesis and biological evaluation of pyrazolo[3,4- b]pyridine derivatives as TRK inhibitors

Nian Liu; Xin Wang; Qinglin Fu; Qiaohua Qin; Tianxiao Wu; Ruicheng Lv; Dongmei Zhao; Maosheng Cheng

doi:10.1039/d2md00334a

Design, synthesis and biological evaluation of pyrazolo[3,4- b]pyridine derivatives as TRK inhibitors

RSC Med Chem. 2022 Oct 18;14(1):85-102. doi: 10.1039/d2md00334a. eCollection 2023 Jan 25.

Authors

Nian Liu¹, Xin Wang¹, Qinglin Fu¹, Qiaohua Qin¹, Tianxiao Wu¹, Ruicheng Lv¹, Dongmei Zhao¹, Maosheng Cheng¹

Affiliation

¹ Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University 103 Wenhua Road, Shenhe District Shenyang 110016 PR China.

Abstract

Tropomyosin receptor kinases (TRKs) are associated with the proliferation and differentiation of cells, and thus their continuous activation and overexpression cause cancer. Herein, based on scaffold hopping and computer-aid drug design, 38 pyrazolo[3,4-b]pyridine derivatives were synthesised. Further, we evaluated their activities to inhibit TRKA. Among them, compound C03 showed acceptable activity with an IC₅₀ value of 56 nM and it inhibited the proliferation of the Km-12 cell line with an IC₅₀ value of 0.304 μM together with obvious selectivity for the MCF-7 cell line and HUVEC cell line. Furthermore, compound C03 possessed good plasma stability and low inhibitory activity to a panel of cytochrome P450 isoforms except CYP2C9. Overall, C03 has potential for further exploration.