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

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.

YAP promotes the proliferation of neuroblastoma cells through decreasing the nuclear location of p27Kip1 mediated by Akt

“…Actually, the functions of YAP are dependent on TEAD at most conditions. There are several reports showing that YAP promotes cell proliferation through TEAD . Therefore, there is great possibility that the regulation of Akt by YAP is dependent on TEAD family members.…”

The Role of Photoactivated and Non-Photoactivated Verteporfin on Tumor

“…Using similar structural analysis methods, Hit-2 ( Gibault et al, 2018 ) and small molecule compounds (CPD3.1) were identified that disrupted the YAP-TEAD interaction. In addition, Hit-2 also inhibited the YAP target gene AXL, Cyr61, and CTGF in MDA-MB-231 cells, and CPD3.1 in HeLa cells, which reduced their proliferation and migration ( Smith et al, 2019 ). Celastrol inhibited the proliferation, migration and clonal expression of the H1299 lung cancer cells and triple-negative breast cancer MDA-MB-231 cells by targeting the YAP-TEAD interactions ( Nouri et al, 2019 ).…”

Does Mechanocrine Signaling by Liver Sinusoidal Endothelial Cells Offer New Opportunities for the Development of Anti-fibrotics?

“…However, further studies are needed to assess its specificity and potential for development as a long term therapeutic strategy. In light of this it is important to note that more specific alternatives to verteporfin have already been developed and tested in vitro (66).…”