Abstract 4280: DWP216, a novel TEAD1 selective inhibitor for NF2 mutant tumors and drug-tolerant persister cells

Abstract Neurofibromatosis type 2 (NF2) controls the Hippo pathway signaling through YAP and TEAD axis. NF2 mutation leads to YAP and TEAD activation and is reported in malignant mesothelioma with 30-40% and meningioma with 50%. Furthermore, drug-tolerant persister cells to EGFR inhibitor or KRAS inhibitor show up-regulation of YAP and TEAD. Four isoforms of TEAD (1-4) are highly conserved and each TEAD isoform has the different biological function depending on organ and co-factors. DWP216, a TEAD1 selective inhibitor, shows the excellent in vitro activities. DWP216 also inhibits TEAD1 activity, TEAD1 palmitoylation and interaction between TEAD1 and YAP1 by binding to palmitate binding pocket of TEAD1. Pharmacokinetic parameter of DWP216 present good druglike properties with blood-brain barrier penetration. DWP216 has the superior in vivo efficacy compared to TEAD1 selective inhibitor and pan-TEAD inhibitor. Moreover, we found that TEAD1 is a key regulator for drug-tolerant persister cells to targeted therapy. Combination of DWP216 and EGFR inhibitor or KRAS inhibitor show synergistic anti-cancer effect in vitro and in vivo. In conclusion, DWP216 is a promising TEAD1 selective inhibitor for NF2 mutant tumor and may be a proper option for drug-resistance of targeted therapy. DWP216 is preparing toward to IND filing for Phase 1 in 2025. Citation Format: Bora Yoo, YoungKu Kang, Won An, Seul Lee, Inyoung Lee, Ahreum Kwon, Eunji Ha, Hyoungrok Bak, Ji-Duck Kim, Joon Seok Park. DWP216, a novel TEAD1 selective inhibitor for NF2 mutant tumors and drug-tolerant persister cells [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 4280.