Abstract 7265: ETS-005, a highly selective TEAD4 palmitoylation inhibitor with potent anti-tumor activity and brain penetrating capability

Abstract The Hippo pathway is a highly conserved network that regulates cell proliferation, tissue regeneration, and organ size by orchestrating YAP/TAZ-TEADs, the core effectors of signaling. Aberrant activation of YAP/TAZ has been implicated in tumorigenesis, tumor progression, metastasis and the resistance to targeted therapeutics, including MAPK and RTK inhibitors. Among the four TEAD paralogs, TEAD4 is found widely overexpressed in various solid tumors and potentially less associated with YAP/TEAD-related renal toxicity. Here we reported the identification of ETS-005, a highly selective TEAD4 small molecule inhibitor that shows preference for binding to the palmitoylation pocket of TEAD4 than other TEAD paralogs over 15 folds. ETS-005 displayed low nanomolar inhibition of cell proliferation in NF2 or LATS1/2 mutant mesothelioma in vitro, and robust anti-tumor efficacy in vivo. ETS-005 showed favorable oral availability, high brain penetration capability and broad safety window. Moreover, ETS-005 had relative long projected T1/2 in human, supporting a more convenient clinical QD dosing schedule. Our study demonstrated that selective TEAD4 palmitoylation inhibitor ETS-005 exhibited potent anti-tumor activity as much as pan-TEAD palmitoylation inhibitors while may gain broader therapeutic index. Additionally, ETS-005 also exhibited profound synergistic effects in drug combination studies, offering broad opportunities combined with MAPK and RTK therapies. ETS-005 is currently in IND-enabling study and expected to enter Phase 1 in 2024. Citation Format: Jiajun Lu, Wenpei Du, Ming Gao, Xiaofei Fan, Jinping Li, Lijian Feng, Mengya Wang, Yingjie Li, Xiaofeng Zhong, Wenqi Cui, Qiangang Zheng, Jidong Zhu. ETS-005, a highly selective TEAD4 palmitoylation inhibitor with potent anti-tumor activity and brain penetrating capability abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 7265.