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 h...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 pathological 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 diseases.Here,we identified a novel TEAD 1/3 covalent inhibitor(DC-TEADin1072)with biochemical IC50 values of 0.61±0.02 and 0.58±0.12μmol/L against TEAD1 and TEAD3,respectively.Further chemical optimization based on DC-TEAD in 1072 yielded a selective TEAD3 inhibitor DCTEAD3 in03 with the IC_(50) value of 0.16±0.03μmol/L,which shows 100-fold selectivity over other TEAD isoforms in activity-based protein profiling(ABPP)assays.In cells,DC-TEAD3 in03 showed selective inhibitory effect on TEAD3 in GAL4-TEAD(1-4)reporter assays with the IC50 value of1.15μmol/L.When administered to zebrafish juveniles,experiments showed that DC-TEAD3 in03 reduced the growth rate of zebrafish caudal fins,indicating the importance of TEAD3 activity in controlling proportional growth of vertebrate appendages.展开更多
基金the financial supports from the National Natural Science Foundation of China(91853205,81625022,81821005 to Cheng Luo81973166,21702218,91753207 to Bing Zhou),Wong Education to Cheng Luo and Bing Zhou+2 种基金the Department of Science and Technology of Fujian Province(2019T3029 to Cheng Luo,China)the Science and Technology Commission of Shanghai Municipality(19XD1404700 and 18431907100 to Cheng Luo,China)National Science&Technology Major Project“Key New Drug Creation and Manufacturing Program”(2018ZX09711002-008 to Cheng Luo,2018ZX09711002-008-005 to Huijin Feng,2018ZX09711002-006 to Bing Zhou,China)。
文摘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 pathological 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 diseases.Here,we identified a novel TEAD 1/3 covalent inhibitor(DC-TEADin1072)with biochemical IC50 values of 0.61±0.02 and 0.58±0.12μmol/L against TEAD1 and TEAD3,respectively.Further chemical optimization based on DC-TEAD in 1072 yielded a selective TEAD3 inhibitor DCTEAD3 in03 with the IC_(50) value of 0.16±0.03μmol/L,which shows 100-fold selectivity over other TEAD isoforms in activity-based protein profiling(ABPP)assays.In cells,DC-TEAD3 in03 showed selective inhibitory effect on TEAD3 in GAL4-TEAD(1-4)reporter assays with the IC50 value of1.15μmol/L.When administered to zebrafish juveniles,experiments showed that DC-TEAD3 in03 reduced the growth rate of zebrafish caudal fins,indicating the importance of TEAD3 activity in controlling proportional growth of vertebrate appendages.
