2. Academic Validation
  3. Antiproliferative and Antimigratory Effects of a Novel YAP-TEAD Interaction Inhibitor Identified Using in Silico Molecular Docking

Antiproliferative and Antimigratory Effects of a Novel YAP-TEAD Interaction Inhibitor Identified Using in Silico Molecular Docking

  • J Med Chem. 2019 Feb 14;62(3):1291-1305. doi: 10.1021/acs.jmedchem.8b01402.
Sarah A Smith 1,  Richard B Sessions 2,  Deborah K Shoemark 2,  Christopher Williams 3,  Reza Ebrahimighaei 1,  Madeleine C McNeill 1,  Matthew P Crump 3,  Tristan R McKay 4,  Gemma Harris 5,  Andrew C Newby 1,  Mark Bond 1
Affiliations

Affiliations

  • 1 School of Translational Health Sciences, Faculty of Health Sciences , University of Bristol , Research Floor Level 7, Bristol Royal Infirmary , Bristol BS2 8HW , U.K.
  • 2 School of Biochemistry, Faculty of Biomedical Sciences , University of Bristol , Biomedical Sciences Building, University Walk , Bristol BS8 1TD , U.K.
  • 3 School of Chemistry, Faculty of Science , University of Bristol , Cantock's Close , Bristol BS8 1TS , U.K.
  • 4 Centre for Bioscience , Manchester Metropolitan University , John Dalton Building , Manchester M1 5GD , U.K.
  • 5 Research Complex at Harwell , Rutherford Appleton Laboratory , Harwell Campus , Didcot, Oxfordshire OX11 0FA , U.K.
PMID: 30640473 DOI: 10.1021/acs.jmedchem.8b01402
Abstract

The Hippo pathway is an important regulator of cell growth, proliferation, and migration. TEAD transcription factors, which lie at the core of the Hippo pathway, are essential for regulation of organ growth and wound repair. Dysregulation of TEAD and its regulatory cofactor Yes-associated protein (YAP) have been implicated in numerous human cancers and hyperproliferative pathological processes. Hence, the YAP-TEAD complex is a promising therapeutic target. Here, we use in silico molecular docking using Bristol University Docking Engine to screen a library of more than 8 million druglike molecules for novel disrupters of the YAP-TEAD interaction. We report the identification of a novel compound (CPD3.1) with the ability to disrupt YAP-TEAD protein-protein interaction and inhibit TEAD activity, cell proliferation, and cell migration. The YAP-TEAD complex is a viable drug target, and CPD3.1 is a lead compound for the development of more potent TEAD inhibitors for treating Cancer and Other hyperproliferative pathologies.

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