Abstract 6980: Discovery of a subtype-selective TEAD inhibitor for cancer treatment

Abstract The transcriptional enhanced associated domain (TEAD) in the Hippo pathway signaling can regulate development and tumorigenesis. TEAD transcription factors have four subtypes (TEAD1-4) with highly conserved sequence whereas these subtypes show different expression levels depending on the organ. TEAD inhibitors are the emerging therapeutic agents for patients with NF2 mutant tumors. Most TEAD inhibitors block all subtypes of TEAD by targeting palmitoylation site and the interface 3 of YAP and TEAD. Here, we discovered TEAD selective inhibitors targeting the allosteric position of palmitoylation site. Our bicyclic compounds showed the potent in vitro activities on TEAD and cancer cell growth inhibitory effects. We also identified the compound-protein structure through X-ray crystallography and the effect of imidazole part on the TEAD selectivity. Pharmacokinetic properties of TEAD selective inhibitors were acceptable for oral administration. Furthermore, a TEAD selective inhibitor reduced the tumor growth of NCI-H226 xenograft mouse model. Overall, a TEAD selective inhibitor has the potential for developing targeted therapy for NF2 mutant tumors also each TEAD subtype-driven pathologies. Citation Format: Won An, YoungKu Kang, Seul Lee, Ye Gi Han, Jiyoon Seok, Sanghoon Kim, Ahreum Kwon, Eunji Ha, Bora Yoo, Ji-Duck Kim, Joon Seok Park. Discovery of a subtype-selective TEAD inhibitor for cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6980.