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

Smith, SA and Sessions, RB and Shoemark, DK and Williams, C and Ebrahimighaei, R and McNeill, MC and Crump, MP and McKay, TR and Harris, G and Newby, AC and Bond, M (2019) Antiproliferative and Antimigratory Effects of a Novel YAP-TEAD Interaction Inhibitor Identified Using in Silico Molecular Docking. Journal of Medicinal Chemistry, 62 (3). pp. 1291-1305. ISSN 0022-2623

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Abstract

© Copyright 2019 American Chemical Society. 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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