TEAD1 palmitoylation-pocket repurposing screen: three-engine consensus virtual screening of approved and late-phase drugs identifies candidate YAP–TEAD interaction inhibitors for Hippo-pathway cancers

Background. The TEAD family of transcription factors (TEAD1-4) are the terminal effectors of the Hippo pathway: upon NF2/merlin loss or upstream dysregulation, de-phosphorylated YAP/TAZ enter the nucleus and bind TEADs to drive proliferation. TEADs are auto-palmitoylated at a conserved internal cysteine, and this palmitoylation — occurring in a druggable internal lipid pocket — is required for YAP/TAZ binding, making the TEAD palmitate pocket a prime target in NF2-driven mesothelioma, NF2-mutant meningioma and other Hippo-pathway cancers. First-in-class TEAD palmitoylation inhibitors (IAG933, VT3989) are in early clinical trials, but no approved drug targets this pocket; repurposing approved and late-phase compounds could accelerate therapy, particularly for brain tumours where BBB penetration matters. Methods. Using the Tomdok pipeline (companion preprint), we docked a curated library of 3,369 approved/Phase III compounds (ChEMBL 37, parent-deduplicated) against the TEAD1 palmitate pocket of the TEAD1/YAP complex (PDB 9FZA) with a three-engine consensus (GNINA, AutoDock Vina, LeDock), dual thresholds (affinity <= -9.0 kcal/mol, CNN >= 0.7), rule-based + data-driven ADMET (hERG from ChEMBL KCNH2 activities, PAINS, withdrawn, Lipinski) and CLEAN/FLAGGED safety stratification. Results. The funnel yielded 107 primary hits and 95 three-engine consensus hits; 78 were CLEAN and 17 FLAGGED. Self-docking of the crystallised TEAD inhibitor reproduced the crystal pose (best-pose RMSD 0.00 A; top-pose 0.99 A; PASS). The hit set is enriched in lipophilic, lipid-mimetic chemotypes (azole antifungals, fibrates, profens, pyrethroids, perfluoro compounds), consistent with occupancy of the hydrophobic palmitate pocket, and includes BBB-penetrant approved CNS drugs (ketanserin, flibanserin, ataluren, perampanel, dasotraline) relevant to NF2-mutant meningioma, plus oncology-approved agents (axitinib, tirabrutinib, danicopan, trametinib, binimetinib). Conclusions. Consensus docking against the TEAD1 palmitate pocket is validated by redocking and yields a safety-annotated, BBB-aware shortlist of repurposing candidates for Hippo-pathway cancers, for experimental validation in TEAD reporter and palmitoylation assays.