Design, synthesis and biological evaluation of 2-aminopyridine derivatives as USP7 inhibitors

A series of novel 2-aminopyridine derivatives 1–26 have been designed and synthesized by structural modifications on a lead USP7 inhibitor, GNE6640. All the compounds were evaluated for their USP7 inhibitory activities. The results showed that most of the compounds have good USP7 inhibitory activities at the concentration of 50 μM. Among them, compounds 7, 14 and 21 are the most potential ones from each category with the IC₅₀ values of 7.6 ± 0.1 μM, 17.0 ± 0.2 μM and 11.6 ± 0.5 μM, respectively. Compounds 7 and 21 expressed significant binding interactions with USP7 by surface plasmon resonance (SPR)-based binding assay, but both of them presented moderate antiproliferative activities against HCT116 cells. They could effectively promote MDM2 degradation, p53 stabilization and p21 gene expression in the western blot analysis.