Discovery of Orally Bioavailable N -Benzylpiperidinol Derivatives as Potent and Selective USP7 Inhibitors with In Vivo Antitumor Immunity Activity against Colon Cancer.

USP7 emerges as a potential therapeutic target for cancers, as it plays an important role in the development of tumorigenesis by stabilizing multiple cancer-relevant proteins. Nevertheless, the discovery of drug-like USP7 inhibitors remains challenging. Herein, we report a series of -benzylpiperidinol derivatives as potent and selective USP7 inhibitors (e.g., and : IC = 7.6 and 8.2 nM), whose binding modes were revealed by crystallographic studies to be distinct from the known -acylpiperidinol USP7 inhibitors. Among them, with good oral PK profiles (rat: = 40.8% and = 3.5 h) exhibited significant antitumor efficacy in the MC38 colon cancer syngeneic mouse model, at least partly through upregulating the tumor infiltration of CD8 T, NK, and NKT cells and downregulating that of Tregs and MDSCs. These findings may further pave the way for the development of USP7 inhibitors as novel cancer immunotherapy drugs.