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

Sarah A. Smith, Richard B. Sessions, Deborah K. Shoemark, Christopher Williams, Reza Ebrahimighaei, Madeleine C. McNeill, Matthew P. Crump, Tristan R. McKay, Gemma Harris, Andrew C. Newby, Mark Bond*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

25 Citations (Scopus)
397 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)1291-1305
Number of pages15
JournalJournal of Medicinal Chemistry
Volume62
Issue number3
Early online date14 Jan 2019
DOIs
Publication statusPublished - 14 Feb 2019

Structured keywords

  • BrisSynBio
  • Bristol BioDesign Institute

Keywords

  • Synthetic biology

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