Discovery of indane and naphthalene derivatives as USP7 inhibitors.

Protein deubiquitination via deubiquitinases is a crucial aspect of the dynamic modification of biomacromolecules. The deubiquitinase USP7 plays a key role in tumorigenesis through diverse pathways, thus representing a promising novel target for anti-cancer therapies. In this paper, in order to find novel USP7 inhibitors, a series of compounds scaffold-hopping from the reported USP7 inhibitor CP41 were designed, synthesized and biologically evaluated. Most of them exhibited certain inhibition against the in vitro USP7 enzyme activity. The most potent compounds (X12, X16, X21, X22 and X23) were highly selective for USP7 over a panel of other tested DUBs and showed significant in vitro inhibition against cancer cell proliferation. Interestingly, in RS4; 11 cancer cells, the selected compound X21 not only regulated the level of the extensively studied proteins (e.g. MDM2, p53, TRIM27) but also remarkably reduced the protein level of PCLAF, a key factor involved in TLS. In colon cancer animal models, X21 exerted in vivo anti-tumor efficacy, probably through synergistic effects of direct cytotoxicity and immune microenvironment improvement. These findings may provide directions for future design of novel USP7 inhibitors and facilitate the exploration of new mechanism of USP7 inhibitors.