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 N-benzylpiperidinol derivatives as potent and selective USP7 inhibitors (e.g., X20 and X26: IC50 = 7.6 and 8.2 nM), whose binding modes were revealed by crystallographic studies to be distinct from the known N- acylpiperidinol USP7 inhibitors. Among them, X36 with good oral PK profiles (rat: F = 40.8% and T1/2 = 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.

Automated summary

USP7 has been identified as a potential therapeutic target for cancer due to its role in tumor development. However, finding drug-like USP7 inhibitors remains challenging. This study reports a series of N-benzylpiperidinol derivatives as potent and selective USP7 inhibitors, which exhibit significant antitumor activity and may have potential as novel cancer immunotherapy drugs.