Discovery of Small Molecule WWP2 Ubiquitin Ligase Inhibitors

Watt, Jessica, Hughes, Gregory, Walpole, Samuel, Monaco, Serena, Stephenson, G. ORCID:, Bulman Page, Philip, Hemmings, Andrew ORCID:, Angulo, Jesus ORCID: and Chantry, Andrew (2018) Discovery of Small Molecule WWP2 Ubiquitin Ligase Inhibitors. Chemistry - A European Journal, 24 (67). pp. 17677-17680. ISSN 0947-6539

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We have screened small molecule libraries specifically for inhibitors that target WWP2, an E3 ubiquitin ligase associated with tumour outgrowth and spread. Selected hits demonstrated dose‐dependent WWP2 inhibition, low micromolar IC50 values, and inhibition of PTEN substrate‐specific ubiquitination. Binding to WWP2 was confirmed by ligand‐based NMR spectroscopy. Furthermore, we used a combination of STD NMR, the recently developed DEEP‐STD NMR approach, and docking calculations, to propose for the first time an NMR‐validated 3D molecular model of a WWP2‐inhibitor complex. These first generation WWP2 inhibitors provide a molecular framework for informing organic synthetic approaches to improve activity and selectivity.

Item Type: Article
Uncontrolled Keywords: hect ubiquitin ligase,saturation transfer difference nmr,deep-std nmr
Faculty \ School: Faculty of Science > School of Biological Sciences
Faculty of Science > School of Chemistry
Faculty of Science > School of Pharmacy
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Depositing User: LivePure Connector
Date Deposited: 13 Sep 2018 10:30
Last Modified: 20 Apr 2023 03:34
DOI: 10.1002/chem.201804169

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