1. Discovery of Small Molecule WWP2 Ubiquitin Ligase Inhibitors
- Author
-
Serena Monaco, Jessica E. Watt, G. Richard Stephenson, Gregory R. Hughes, Samuel Walpole, Andrew M. Hemmings, Philip C. Bulman Page, Andrew Chantry, and Jesús Angulo
- Subjects
0301 basic medicine ,Ubiquitin-Protein Ligases ,WWP2 ,Ligands ,Catalysis ,Small Molecule Libraries ,Inhibitory Concentration 50 ,03 medical and health sciences ,Ubiquitin ,Drug Discovery ,Humans ,Enzyme Inhibitors ,Nuclear Magnetic Resonance, Biomolecular ,Binding Sites ,biology ,Drug discovery ,Chemistry ,Organic Chemistry ,PTEN Phosphohydrolase ,General Chemistry ,Nuclear magnetic resonance spectroscopy ,Small molecule ,Protein Structure, Tertiary ,Ubiquitin ligase ,Molecular Docking Simulation ,030104 developmental biology ,Solubility ,Biochemistry ,Docking (molecular) ,biology.protein - 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.
- Published
- 2018
- Full Text
- View/download PDF