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.
Highlights
The oncogenic Hippo signaling pathway has emerged as an important regulator of cell growth,[1] proliferation,[2] and migration.[3]
The second Bristol University Docking Engine (BUDE) run docked the 100 000 compounds into five structures extracted from the molecular dynamics (MD) simulation of TEAD1, which allowed the selection of 1000 compounds showing binding to at least four TEAD1 protein conformations (Supplement Figures 1 and 2)
The shortlisted sets of 16 compounds were first assayed for their ability to inhibit TEAD-dependent transcriptional activity in HeLa cells that had been transduced with a recombinant lentiviral vector expressing secreted bioluminescent nanoluciferase (NLUC) reporter gene enzyme, which is expressed under the control of a promoter region containing eight TEAD DNA-binding elements (TEAD-NLUC)
Summary
The oncogenic Hippo signaling pathway has emerged as an important regulator of cell growth,[1] proliferation,[2] and migration.[3]. Dysregulated TEAD activity has been associated with other hyperproliferative pathological processes, including angioplasty restenosis.[18]. Transcriptional activation by TEAD is dependent on interaction with transcriptional cofactors. The best characterized TEAD cofactors are Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ).[19] other proteins have been reported to have
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