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Anti-proliferative and anti-migratory effects of a novel YAP-TEAD interaction inhibitor identified using in silico molecular docking

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)1291-1305
Number of pages15
JournalJournal of Medicinal Chemistry
Volume62
Issue number3
Early online date14 Jan 2019
DOIs
DateAccepted/In press - 14 Jan 2019
DateE-pub ahead of print - 14 Jan 2019
DatePublished (current) - 14 Feb 2019

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 co-factor YAP have been implicated in numerous human cancers and hyper-proliferative pathological processes. Hence the YAP-TEAD complex is a promising therapeutic target. Here we use in silico molecular docking using BUDE (Bristol University Docking Engine) to screen a library of more than eight million drug-like 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, inhibit TEAD activity and inhibit cell proliferation and cell migration. The YAP-TEAD complex is a viable drug target and CPD3.1 is a lead compound for development of more potent TEAD inhibitors for treating cancer and other hyper-proliferative pathologies.

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    Rights statement: This is the final published version of the article (version of record). It first appeared online via ACS Publications at https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01402. Please refer to any applicable terms of use of the publisher.

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