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

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 mu M 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.

Automated summary

In this study, 38 pyrazolo[3,4-b]pyridine derivatives were synthesized based on scaffold hopping and computer-aided drug design. The activities of these derivatives in inhibiting TRKA were evaluated, and compound C03 showed promising activity with good selectivity and plasma stability, making it a potential candidate for further exploration.