发现口服生物可利用的 N-苄基哌啶醇衍生物作为强效选择性 USP7 抑制剂，具有针对结肠癌的体内抗肿瘤免疫活性

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 : IC 50 = 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 T 1/2 = 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.