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ID: ALA4725339
Journal: Bioorg Med Chem Lett
Title: Discovery of USP7 small-molecule allosteric inhibitors.
Authors: Engström O,Belda O,Kullman-Magnusson M,Rapp M,Böhm K,Paul R,Henderson I,Derbyshire D,Karlström S,Parkes KEB,Zhao H
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 HNMR saturation transfer difference and NOESY experiments enabled structure-based design of additional compounds showing IC 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.
CiteXplore: 32781219