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

doi:10.1016/j.apsb.2021.04.015

	Discovery of a subtype-selective, covalent inhibitor against palmitoylation pocket of TEAD3
	Lu, Tian 3,6; Li, Yong 1,2,3; Lu, Wenchao 4; Spitters, Twgm 5; Fang, Xueyu 5; Wang, Jun 7; Cai, Simian 5; Gao, Jing 8,9; Zhou, Yanting 8,9; Duan, Zhe 3,10
刊名	ACTA PHARMACEUTICA SINICA B
	2021-10-01
卷号	11 期号:10 页码:3206-3219
关键词	Hippo pathway TEAD3 Covalent inhibitor Palmitoylation inhibitor
ISSN号	2211-3835
DOI	10.1016/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.
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关键词	HIPPO PATHWAY ; YAP ; OVEREXPRESSION ; PROMOTES ; GROWTH ; ROLES
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
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/298320]
专题	中国科学院上海药物研究所
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.