Discovery of Small Molecule WWP2 Ubiquitin Ligase Inhibitors

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....

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Bibliographic Details
Published in:Chemistry : a European journal 2018-12, Vol.24 (67), p.17677-17680
Main Authors: Watt, Jessica E., Hughes, Gregory R., Walpole, Samuel, Monaco, Serena, Stephenson, G. Richard, Bulman Page, Philip C., Hemmings, Andrew M., Angulo, Jesus, Chantry, Andrew
Format: Article
Language:English
Subjects:
Binding Sites
Chemistry
DEEP-STD NMR
Docking
Drug Discovery
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - metabolism
Humans
Inhibitors
Inhibitory Concentration 50
Ligands
Magnetic resonance spectroscopy
Molecular Docking Simulation
NMR spectroscopy
Nuclear Magnetic Resonance, Biomolecular
Protein Structure, Tertiary
PTEN Phosphohydrolase - metabolism
PTEN protein
saturation transfer difference NMR
Selectivity
Small Molecule Libraries - chemistry
Small Molecule Libraries - metabolism
Solubility
Substrate inhibition
Three dimensional models
Tumors
Ubiquitin
ubiquitin ligase
Ubiquitin-protein ligase
Ubiquitin-Protein Ligases - antagonists & inhibitors
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
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Summary: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. HTS screen and DEEP‐STD NMR validation of a 3D structural model was used to discover a new class of WWP2 ubiquitin ligase inhibitors.
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.201804169