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

Abstract

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