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Discovery of Small Molecule WWP2 Ubiquitin Ligase Inhibitors
Author(s) -
Watt Jessica E.,
Hughes Gregory R.,
Walpole Samuel,
Monaco Serena,
Stephenson G. Richard,
Bulman Page Philip C.,
Hemmings Andrew M.,
Angulo Jesus,
Chantry Andrew
Publication year - 2018
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201804169
Subject(s) - ubiquitin ligase , ubiquitin , small molecule , chemistry , docking (animal) , stereochemistry , binding site , pten , dna ligase , molecular model , nuclear magnetic resonance spectroscopy , biochemistry , biophysics , biology , enzyme , signal transduction , gene , medicine , nursing , pi3k/akt/mtor pathway
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.