Abstract A45: In silico drug discovery targeting Hippo pathway and YAP-TEAD protein-protein interactions for small-molecule anticancer agent

Abstract The Hippo pathway is one of the important pathways regulating tissue growth and proliferation. Dysregulation of this pathway can result in overgrowth of phenotypes because of a malfunction of stem cell proliferation, differentiation, and apoptosis, which are directly involved with components to cancer cell developments. Protein-protein interaction (PPI) in YAP (Yes-associated protein) and TEAD (transcriptional enhancer associate domain) is a key interaction that regulates cancer cell growth in the Hippo pathway. Regulating YAP-TEAD protein-protein interaction by small molecules could play an important role in cancer therapy. In this study, we identified small molecules inhibiting YAP-TEAD interactions by an in silico approach. Molecular hits were identified by pharmacophore-based virtual screening. The hit compounds from virtual screening were tested by surface plasmon resonance (SPR), Luciferase activity test. As a result, several hit compounds were identified to inhibit YAP-TEAD protein-protein interactions. These selected hit compounds were also evaluated by molecular docking study and FMO (fragment molecular orbital) binding energy calculations. In our overall results, we identified hit compounds to inhibit YAP-TEAD PPIs and also analyzed hit compounds’ binding interaction energy to TEAD protein. Citation Format: Kim Jongwan, Hocheol Lim, K.T. No. In silico drug discovery targeting Hippo pathway and YAP-TEAD protein-protein interactions for small-molecule anticancer agent [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr A45.