Identification of Small-molecule YAP-TEAD inhibitors by High-throughput docking for the Treatment of colorectal cancer

The YAP-TEAD transcriptional complex is responsible for the expression of genes that regulate cancer cell growth, proliferation, and apoptosis. Dysregulation of the Hippo pathway due to overexpression of YAP has been reported in various cancers. Inhibition of TEAD represses the expression of associated genes, proving the value of this transcription factor for the development of novel anti-cancer therapies. We retrieved a promising hit compound L06 which is a potent TEAD4 inhibitor through docking-based virtual screening. L06 inhibits TEAD autopalmitoylation, interrupts YAP-TEAD interaction, and reduces the YAP-TEAD transcriptional activity. Moreover, L06 reduces the expression of CTGF, inhibits HCT 116 colorectal cancer cell proliferation, migration and invasion. The YAP-TEAD complex is a viable drug target, and L06 is a lead compound for the development of more potent TEAD inhibitors to treat colorectal cancer and other hyperproliferative pathologies.