Abstract P176: Discovery and development of novel covalent inhibitors of the YAP-TEAD transcription activity

Abstract

Abstract TEAD (TEA domain transcription factor) is a transcription factor. As a major effector of the Hippo signaling pathway, TEAD is reported to be responsible for cell proliferation, apoptosis, and stem cell self-renewal. Emerging evidence has shown that TEADs play a prominent role in the development, progression, and metastasis of cancers such as mesothelioma, liposarcoma, pancreatic, etc. Small-molecule inhibitors of TEADs could be a novel targeted therapy for multiple cancers. Using its proprietary chemoproteomic platform IMTACTM (Isobaric Mass Tagged Affinity Characterization), BridGene has screened its unique covalent library against live-cell proteomes. Three distinct series of hits, with MCS Tanimoto Coefficients at ~0.3 between any two series, were identified for TEAD proteins with nanomolar affinity and high proteomic selectivity. The covalent interactions between the hit and TEAD proteins were confirmed using orthogonal fluorescence-based experiments. Mass Spec analysis and mutagenesis experiments identified the site of modification within the central lipid (palmitate) binding pocket of TEAD1. Multiple novel and potent small molecule inhibitors were obtained with good druggability. Several functional assays were established to measure inhibition of TEAD-YAP transcription activity/disruption including Luciferase assay in MCF7-Luc, CTG (cell-titer Glo), and ELISA. When evaluated in vitro, BridGene’s TEAD inhibitors exhibited anti-proliferative properties against NF2-deficient mesothelioma cell lines (NCI-H226, NF2-/-) with low nM IC50, but had little effects on in NF2 wildtype cancer cell lines (NCI-H2452, NF2+/+) or HepG2 cell line. In an ELISA assay, BridGene’s small molecules can potently disrupt TEAD-YAP protein-protein interaction in cells. In MCF7-TEAD1 luciferase reporter cells, compounds showed single-digit nM potency in disrupting TEAD downstream gene expression. BridGene is developing covalent TEAD inhibitors to treat multiple cancers that are dependent on TEAD activity, including mesothelioma, cholangiocarcinoma, liposarcoma, pancreatic cancer, etc. With their high potency and proteomic selectivity, these TEAD inhibitors can potentially act as single-agent therapy, or work in combination with other care agents to treat multiple cancers. Citation Format: Shirley Guo, Cindy Huang, C. Glenn Begley, Michael J. Bishop, Ping Cao. Discovery and development of novel covalent inhibitors of the YAP-TEAD transcription activity [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P176.