Abstract 5159: Rational development of novel FBXO22-mediated TEAD Targeted Glues™ for mesothelioma and NSCLC treatment

Abstract TEAD transcription factors are critical effectors of the Hippo signalling pathway and represent promising therapeutic targets in cancers with pathway dysregulation. We report the rational discovery and optimization of a novel class of TEAD degraders that exploit a Targeted Glue™ mechanism to achieve FBXO22-dependent proteasomal degradation. Our novel degraders with differentiated chemical matter demonstrate exceptional degradation profiles (sub-nM DC50, 90% Dmax), coupled with outstanding on-pathway selectivity as measured by global proteomics vs 7000 other proteins measured. Through comprehensive mechanistic studies, we elucidated that our warheads engage FBXO22 via covalent modification of C326. This structural understanding, enabled by high-resolution ternary complex cryo-EM data, facilitated systematic structure-activity relationship optimization of both degradation potency and kinetic parameters. In vitro, our lead compounds exhibited deep (150% GImax) and potent (nM GI50) anti-proliferative activity in mesothelioma, with synergistic efficacy observed in combination with EGFR inhibitors in EGFR-mutant NSCLC models. Critically, our optimized compounds achieved oral bioavailability and demonstrated robust in vivo activity, representing the first demonstration of FBXO22-mediated degradation in vivo. In mesothelioma xenograft models, we observed rapid (2h, first time point measured), deep (95%) and sustained (≥72h) TEAD degradation leading to prolonged biomarker inhibition. Our work provides critical design principles for this degrader class and validates FBXO22-TEAD degradation as a therapeutically relevant approach for Hippo pathway-driven cancers, with promise in mesothelioma and combination strategies for EGFR-mutant NSCLC. Citation Format: Marta Carrara, Martin Fisher, Alice Fletcher, Callum Hamby, Jack Miles, Colin T. Davies, Sara Bisetto, Paula MacGregor, Edward Hooper-Greenhill, Aleksandra Azevedo, Martin O'Rourke, Dominic CG Owens, Liliana Greger, Ivan Del Barco Barrantes, Giles Brown, Martin Pass, Louise K. Modis. Rational development of novel FBXO22-mediated TEAD Targeted Glues™ for mesothelioma and NSCLC treatment abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5159.