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.

Automated summary

The YAP-TEAD transcriptional complex plays a crucial role in cancer cell growth, proliferation, and apoptosis, and dysregulation of the Hippo pathway due to YAP overexpression has been observed in various cancers. Inhibiting TEAD has shown promise in suppressing the expression of associated genes, making it a valuable transcription factor for the development of anti-cancer therapies. Through virtual screening, compound L06 was identified as a potent TEAD4 inhibitor, inhibiting TEAD autopalmitoylation, disrupting YAP-TEAD interaction, and reducing their transcriptional activity. L06 also demonstrated the ability to reduce CTGF expression and inhibit the proliferation, migration, and invasion of colorectal cancer cells.