Abstract 326: Structural dynamics-based hit generation to disrupt YAP/TAZ-TEAD protein-protein interaction

The Hippo pathway is an evolutionarily conserved pathway involved in developmental biology. The biological functions of Hippo pathway are executed by the downstream transcriptional coactivator YAP/TAZ, which shuttle between the cytoplasm and the nucleus and have to interact with TEADs in nucleus for transcription activation. YAP/TAZ are master transcriptional factors widely activated in human cancers to promote cancer initiation, progression, metastasis and therapy resistance. It has been shown that aberrant YAP/TAZ activation is also associated with the adapted tumor microenvironment (TME) for tumor growth. Dysregulation in Hippo pathway and YAP/TAZ-TEADs transcriptional activity is pervasively associated with various types of cancers, including mesothelioma, squamous cell cancers, liver cancer and lung cancer, making it an attractive target for cancer therapy. Therefore, inhibition of YAP/TAZ oncogenic activity by blocking YAP/TAZ-TEADs interaction is an effective approach for cancer treatment. In this study, we aim to discover small molecule inhibitors that bind to TEADs and disrupt YAP/TAZ-TEADs interaction for cancer therapy. With superposition of all the available crystal structures of four TEAD subtypes in the public database, we found the YAP Ω loop binding site of TEADs is relatively rigid (of backbone atoms), but the side chain flexibility of K289, K265 and V406 in TEAD1 affects the shape of the binding site significantly. Notably, in two TEAD2 structures, e.g. PDB ID: 5dqe and 5dq8, K301 (K274 of TEAD1) adopts an open conformation and accommodates a flufenamic acid to bind in an induced pocket. Using 5dq8 as the protein model, we virtually screened a fragment library, and identified a hit compound that is suitable to combine with flufenamic acid. Interaction between the hit compound and TEAD1 was confirmed by 1D-NMR (STD). Based on the docking poses, we combined the hit and flufenamic acid, designed and synthesized several compounds. Interaction with TEAD1 of the compounds were confirmed by 1D-NMR, SPR and HTRF. Crystal structures of representative compounds confirmed the predicted binding mode in TEAD1. With further medicinal chemistry efforts, we have discovered a series of novel YAP/TAZ-TEAD PPI inhibitors bound at the Ω loop site of TEAD1. Citation Format: Lin Du, Jing Liu, Qinglong Zeng, Ming Xu, Jiting Lu, Qiangang Zheng, Jidong Zhu. Structural dynamics-based hit generation to disrupt YAP/TAZ-TEAD protein-protein interaction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 326.