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Discovery of a subtype-selective, covalent inhibitor against palmitoylation pocket of TEAD3

文献类型：期刊论文

作者Lu, Tian3,6; Li, Yong1,2,3; Lu, Wenchao4; Spitters, Twgm5; Fang, Xueyu5; Wang, Jun7; Cai, Simian5; Gao, Jing8,9; Zhou, Yanting8,9; Duan, Zhe3,10
刊名ACTA PHARMACEUTICA SINICA B
出版日期2021-10-01
卷号11期号:10页码:3206-3219
ISSN号2211-3835
关键词Hippo pathway TEAD3 Covalent inhibitor Palmitoylation inhibitor
DOI10.1016/j.apsb.2021.04.015
通讯作者Zhou, Bing(zhoubing@simm.ac.cn) ; Antos, Christopher L.(clantos@shanghaitech.edu.cn) ; Luo, Cheng(cluo@simm.ac.cn)
英文摘要The TEA domain (TEAD) family proteins (TEAD-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 TEAD1/3 covalent inhibitor (DC-TEAD in 1072) with biochemical IC50 values of 0.61 +/- 0.02 and 0.58 +/- 0.12 mu mol/L against TEAD1 and TEAD3, respectively. Further chemical optimization based on DC-TEAD in 1072 yielded a selective TEAD3 inhibitor DC-TEAD3 in 03 with the IC50 value of 0.16 +/- 0.03 mmol/L, which shows 100-fold selectivity over other TEAD isoforms in activity-based protein profiling (ABPP) assays. In cells, DC-TEAD3 in 03 showed selective inhibitory effect on TEAD3 in GAL4-TEAD (1-4) reporter assays with the IC50 value of 1.15 mmol/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 controlling proportional growth of vertebrate appendages. (C) 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
WOS关键词HIPPO PATHWAY ; YAP ; OVEREXPRESSION ; PROMOTES ; GROWTH ; ROLES
资助项目National Natural Science Foundation of China[91853205] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81821005] ; National Natural Science Foundation of China[81973166] ; National Natural Science Foundation of China[21702218] ; National Natural Science Foundation of China[91753207] ; Wong Education ; Department of Science and Technology of Fujian Province[2019T3029] ; Science and Technology Commission of Shanghai Municipality (China)[19XD1404700] ; Science and Technology Commission of Shanghai Municipality (China)[18431907100] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program (China)[2018ZX09711002-008] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program (China)[2018ZX09711002-008-005] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program (China)[2018ZX09711002-006]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
WOS记录号WOS:000710908100004
源URL[http://119.78.100.183/handle/2S10ELR8/298320]  
专题新药研究国家重点实验室
通讯作者Zhou, Bing; Antos, Christopher L.; Luo, Cheng
作者单位1.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Ctr Chem Biol, Drug Discovery & Design Ctr, Shanghai Inst Mat Med,State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA
5.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
6.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
7.Shanghai Jiao Tong Univ, Sch Life Sci & Biotechnol, Shanghai 200240, Peoples R China
8.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Analyt Chem, Shanghai 201203, Peoples R China
9.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
10.Nanchang Univ, Sch Pharm, Nanchang 330006, Jiangxi, Peoples R China
推荐引用方式
GB/T 7714		 Lu, Tian,Li, Yong,Lu, Wenchao,et al. Discovery of a subtype-selective, covalent inhibitor against palmitoylation pocket of TEAD3[J]. ACTA PHARMACEUTICA SINICA B,2021,11(10):3206-3219.
APA Lu, Tian.,Li, Yong.,Lu, Wenchao.,Spitters, Twgm.,Fang, Xueyu.,...&Luo, Cheng.(2021).Discovery of a subtype-selective, covalent inhibitor against palmitoylation pocket of TEAD3.ACTA PHARMACEUTICA SINICA B,11(10),3206-3219.
MLA Lu, Tian,et al."Discovery of a subtype-selective, covalent inhibitor against palmitoylation pocket of TEAD3".ACTA PHARMACEUTICA SINICA B 11.10(2021):3206-3219.

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来源：上海药物研究所

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