Discovery of USP7 small-molecule allosteric inhibitors. Issue 20 (15th October 2020)

• Record Type: Journal Article
• Authors: Engström, Olof; Belda, Oscar; Kullman-Magnusson, Mari; Rapp, Mikaela; Böhm, Kerstin; Paul, Ralf; Henderson, Ian; Derbyshire, Dean; Karlström, Sofia; Parkes, Kevin E.B.; Zhao, Hongtao
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 20(2020)
• Publication Date: 2020-10-15
• Subjects: USP7 ubiquitin specific protease-7 -- DUBs deubiquitylating enzymes -- USPs ubiquitin specific protease -- TROSY transverse relaxation optimized spectroscopy -- CSP chemical shift perturbation -- STD saturation transfer difference -- NOESY nuclear Overhauser effect spectroscopy -- SAR structure-activity relationship; USP7 -- NMR -- Ubiquitylation -- Allosteric -- Inhibitors; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127471
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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 1 H NMR 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.