Abstract 1671: Discovery of ETS-003, a potent and selective YAP/TAZ-TEAD PPI inhibitor with broad anti-tumor activity in Hippo-YAP aberrant cancers

Abstract Hippo/YAP is a conserved signaling pathway controlling organ development, tissue regeneration and immune modulation. Cascade of tumor suppressor genes (NF2, LATS1/2) and multiple signals from cellular microenvironment (mechano-transduction) regulate YAP/TAZ phosphorylation and degradation. The stabilized YAP/TAZ translocate from cytoplasm to nucleus, where they bind with TEADs for transcriptional activation. YAP/TAZ regulate numerous genes expression which play central roles in cell proliferation, apoptosis, tumor microenvironment remodeling, and drug resistance, making them appealing targets for cancer treatment. Disruption of YAP/TAZ-TEAD protein-protein interaction (PPI) has been regarded as an effective approach to abolish YAP/TAZ oncogenic activity. Previously we have reported the discovery of YAP/TAZ-TEAD PPI hit compounds bound at the Ω loop site of TEAD1. Here we report that the CADD-guided optimization of the hit compounds has yielded an orally available and potent YAP/TEAD PPI inhibitor ETS-003 with favorable ADME properties and robust anti-tumor efficacy. ETS-003 could potently block YAP/TAZ-TEAD PPI both in vitro and in cells, and disrupt YAP/TAZ genome-wide chromatin binding, resulting in on-target inhibition of YAP transcriptome. ETS-003 exhibited broad anti-proliferative activity in a variety of solid tumor cell lines. In Hippo-YAP dysregulated mesothelioma models, ETS-003 showed profound anti-tumor activity and good PK/PD/efficacy correlation. Moreover, when combined with MAPK pathway inhibitors (Osimertinib, Sotorasib and MRTX1133), ETS-003 could significantly enhance the anti-proliferative activity, suggesting multiple combination opportunities for ETS-003 in clinical investigations. The non-GLP studies of ETS-003 showed favorable safety margin, and warranted further clinical studies of ETS-003 in solid tumors. Citation Format: Jiajun Lu, Ming Gao, Hao He, Lijian Feng, Zhenting Gao, Wenqi Cui, Kun Yang, Jiting Lu, Qiangang Zheng, Jidong Zhu, Xin Guo. Discovery of ETS-003, a potent and selective YAP/TAZ-TEAD PPI inhibitor with broad anti-tumor activity in Hippo-YAP aberrant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1671.