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

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.