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Discovery of Small Molecule WWP2 Ubiquitin Ligase Inhibitors

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Abstract

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.

Details

Original languageEnglish
Pages (from-to)17677-17680
JournalChemistry - A European Journal
Volume24
Issue number67
Early online date12 Sep 2018
DOIs
StatePublished - 3 Dec 2018
Peer-reviewedYes

Keywords

    Research areas

  • HECT Ubiquitin Ligase, saturation transfer difference NMR, DEEP-STD NMR

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