Discovery of USP7 small-molecule allosteric inhibitors

[Display omitted] 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 chal...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2020-10, Vol.30 (20), p.127471-127471, Article 127471
Hauptverfasser: 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
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Sprache:eng
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Zusammenfassung:[Display omitted] 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2020.127471