通过FBXO22介导的新型TEAD靶向胶（Targeted Glues™）用于间皮瘤和NSCLC治疗的合理开发

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.