Discovery of USP7 small-molecule allosteric inhibitors.

Engström O, Belda O, Kullman-Magnusson M, Rapp M, Böhm K, Paul R, Henderson I, Derbyshire D, Karlström S, Parkes KEB, Zhao H

Bioorg. Med. Chem. Lett. 30 (20) 127471 [2020-10-15; online 2020-08-08]

Ubiquitin specific protease-7 (USP7) is considered an attractive target for cancer therapy by promoting degradation of the tumor suppressor p53 and negatively affecting the immune response to tumors. However, the development of selective non-covalent USP7 inhibitors has proven challenging. In this work we report the NMR characterization of a weak binder from SPR screening of an in-house fragment library which reveals that it binds to the allosteric palm site of the catalytic domain. Molecular modeling combined with 1HNMR saturation transfer difference and NOESY experiments enabled structure-based design of additional compounds showing IC50 values in the low-micromolar range with good selectivity over the closest homolog USP47. The most potent analogue represents a promising starting point for the development of novel, selective USP7 inhibitors.

Swedish NMR Centre (SNC) [Service]

PubMed 32781219

DOI 10.1016/j.bmcl.2020.127471

Crossref 10.1016/j.bmcl.2020.127471

pii: S0960-894X(20)30582-5

Publications 9.5.0