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The TEA domain (TEAD) family proteins (TEAD1-4) are essential transcription factors that control cell differentiation and organ size in the Hippo pathway.Although the sequences and structures of TEAD family proteins are highly conserved,each TEAD isoform has unique physiological and patholog-ical functions.Therefore,the development and discovery of subtype selective inhibitors for TEAD protein will provide important chemical probes for the TEAD-related function studies in development and dis-eases.Here,we identified a novel TEAD1/3 covalent inhibitor (DC-TEADin1072) with biochemical IC5o values of 0.61 ± 0.02 and 0.58 ± 0.12 μmol/L against TEAD1 and TEAD3,respectively.Further chemical optimization based on DC-TEAD in 1072 yielded a selective TEAD3 inhibitor DC-TEAD3in03 with the IC50 value of 0.16 ± 0.03 μmol/L,which shows 100-fold selectivity over other TEAD isoforms in activity-based protein profiling (ABPP) assays.In cells,DC-TEAD3in03 showed se-lective inhibitory effect on TEAD3 in GAL4-TEAD (1-4) reporter assays with the IC5o value of 1.15 μmol/L.When administered to zebrafish juveniles,experiments showed that DC-TEAD3in03 reduced the growth rate of zebrafish caudal fins,indicating the importance of TEAD3 activity in control-ling proportional growth of vertebrate appendages.