A novel anti-cancer compound development targeting YAP-TEAD protein-protein interaction

Abstract

Background: Dysregulation of the Hippo signaling pathway can result in tumorigenesis and overgrowth of cancer. A significant percentage of cancer patients present an overexpression of YAP (Yes Associated Protein) proteins. YAP transcriptional activity requires its binding to transcriptional enhanced associated domain (TEAD) transcription factors. Therefore, one attractive strategy for the targeting of YAP consists of preventing its interaction with TEAD using interfering peptides. Although several protein-protein interaction disruptors (PPID) have been developed to target inhibition of YAP-TEADs, drug candidates selectively targeting YAP-TEAD are still lacking. Material and methods: We identified drug candidates screened from integrated 3D database, based on structural interface between YAP and TEADs. We identified a novel lead compound, and its pharmaco-chemical activity and antitumor activity were comprehensively validated in human colorectal cancer (CRC) model. Results: A lead compound KYP-1104 harbored highly conserved molecular docking poses with TEAD1, TEAD4, and YAP1, and its disturbing activity of interaction of YAP-TEAD was validated by luciferase reporting system and immunoprecipitation assay. KYP-1104 harbored anti-proliferative activity of CRC cells in vitro and anti-tumor activity in vivo. Then, we showed that KYP-1104-related antitumor activity was also related to the inhibition of epithelial-to-mesenchymal transition and invasion, and by promotion of cell death. Additionally, KYP-1104 also presented time-dependent and dose-dependent inhibition of phosphatidylinositol-3-kinase signaling pathway and MAPK signaling pathway, and it suppressed transcription of major molecules such as BIRC, CTGF, PD-L1, and CCND1 assisted by YAP-TEADs binding. Finally, using integrative transcriptome analyses, CRC cells treated with KYP-1104 showed a YAP-conserved signature, and the responders had higher activity of E2F and Myc pathways than non-responders in which NF-kB and KRAS pathways was enriched. Conclusions: We herein demonstrated that KYP-1104 is a potential PPID which selectively inhibits YAP-TEADs interaction. This drug compound is expected to have therapeutic efficacy to control Hippo pathway-dependent cancers by inhibiting YAP-TEAD-mediated transcription and its related pathways, especially in human CRC.