Discovery of [1,2,3]triazolo[4,5-d]pyrimidine derivatives as highly potent, selective, and cellularly active USP28 inhibitors.

ABSTRACT: Ubiquitin specific peptidase 28 (USP28) is closely associated to the occurrence and development of various malignancies, and thus has been validated as a promising therapeutic target for cancer therapy. To date, only few USP28 inhibitors with moderate inhibitory activity have been reported, highly potent and selective USP28 inhibitors with new chemotypes remain to be discovered for pathologically investigating the roles of deubiquitinase. In this current study, we reported the synthesis and biological evaluation of new [1,2,3]triazolo[4,5-d]pyrimidine derivatives as potent USP28 inhibitors. Especially, compound 19 potently inhibited USP28 (IC₅₀ = 1.10 ± 0.02 μmol/L, K _d = 40 nmol/L), showing selectivity over USP7 and LSD1 (IC₅₀ > 100 μm

SUBMITTER: Liu Z 

PROVIDER: S-EPMC7488365 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature