Discovery and biological evaluation of vinylsulfonamide derivatives as highly potent, covalent TEAD autopalmitoylation inhibitors

doi:10.1016/j.ejmech.2019.111767

	Discovery and biological evaluation of vinylsulfonamide derivatives as highly potent, covalent TEAD autopalmitoylation inhibitors
	Lu, Wenchao 6,7,8; Wang, Jun 7,10; Li, Yong 8,9; Tao, Hongru 7,11; Xiong, Huan 9; Lian, Fulin 12; Gao, Jing 2,12; Ma, Hongna 3,7; Lu, Tian 7,10; Zhang, Dan 4,7
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2019-12-15
卷号	184 页码:15
关键词	Hippo pathway TEAD transcription factor Covalent inhibitor Palmitoylation inhibitor
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2019.111767
通讯作者	Zhou, Bing(zhoubing@simm.ac.cn) ; Luo, Cheng(cluo@simm.ac.cn)
英文摘要	Transcriptional enhancer associated domain family members (TEADs) are the most important downstream effectors that play the pivotal role in the development, regeneration and tissue homeostasis. Recent biochemical studies have demonstrated that TEAD5 could undergo autopalmitoylation that is indispensable for its function making the lipid-binding pocket an attractive target for chemical intervention. Herein, through structure-based virtual screen and rational medicinal chemistry optimization, we identified DC-TEADin02 as the most potent, selective, covalent TEAD autopalmitoylation inhibitor with the IC50 value of 197 +/- 19 nM while it showed minimal effect on TEAD-YAP interaction. Further biochemical counter-screens demonstrate the specific thiol reactivity and selectivity of DC-TEADin02 over the kinase family, lipid-binding proteins and epigenetic targets. Notably, DC-TEADin02 inhibited TEADs transcription activity leading to downregulation of YAP-related downstream gene expression. Taken together, our findings proved the validity of modulating transcriptional output in the Hippo signaling pathway through irreversible chemical interventions of TEAD5 autopalmitoylation activity, which may serve as a qualified chemical tool for TEADs palmitoylation-related studies in the future. (C) 2019 Elsevier Masson SAS. All rights reserved.
资助项目	Ministry of Science and Technology of China[2015CB910304] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[91853205] ; National Natural Science Foundation of China[81821005] ; National Natural Science Foundation of China[81803438] ; National Natural Science Foundation of China[91753207] ; National Natural Science Foundation of China[81430084] ; National Science and Technology Major Project[2018ZX09711002-004-013] ; National Science and Technology Major Project[2018ZX09711002-006-001] ; National Science and Technology Major Project[2018ZX09711002-007] ; National Science and Technology Major Project[2018ZX09711002] ; K.C. Wong Education Foundation ; Chinese Academy of Sciences[XDA12020353] ; Chinese Academy of Sciences[XDA12050401] ; Chinese Academy of Sciences[XDA12020361] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; National Key R&D Program of China[2018YFA0508200] ; Shanghai Rising-Star Program[17QA1405000] ; China Postdoctoral Science Foundation[2017M621571]
WOS关键词	PROTEIN S-PALMITOYLATION ; HIPPO PATHWAY ; YAP ; LIGAND ; CANCER ; MAP
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000501660900025
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/282164]
专题	中国科学院上海药物研究所
通讯作者	Zhou, Bing; Luo, Cheng
作者单位	1.Pilot Natl Lab Marine Sci & Technol Qingdao, Open Studio Druggabil Res Marine Nat Prod, 1 Wenhai Rd, Qingdao 266237, Shandong, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 3.Guiyang Univ Tradit Chinese Med, Dept Pharm, South Dong Qing Rd, Guiyang 550025, Guizhou, Peoples R China 4.Guizhou Univ, Sch Pharmaceut Sci, Key Lab Guizhou Fermentat Engn & Biomed, Guiyang 550025, Guizhou, Peoples R China 5.Zhejiang Sci Tech Univ, Coll Life Sci, 928 2 St, Hangzhou 310018, Zhejiang, Peoples R China 6.Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA 7.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 8.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China 9.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Dept Med Chem, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 10.Nanjing Univ Chinese Med, Jiangsu Key Lab High Technol Res TCM Formulae, 138 Xianlin Rd, Nanjing 210023, Jiangsu, Peoples R China
推荐引用方式 GB/T 7714	Lu, Wenchao,Wang, Jun,Li, Yong,et al. Discovery and biological evaluation of vinylsulfonamide derivatives as highly potent, covalent TEAD autopalmitoylation inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2019,184:15.
APA	Lu, Wenchao.,Wang, Jun.,Li, Yong.,Tao, Hongru.,Xiong, Huan.,...&Luo, Cheng.(2019).Discovery and biological evaluation of vinylsulfonamide derivatives as highly potent, covalent TEAD autopalmitoylation inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,184,15.
MLA	Lu, Wenchao,et al."Discovery and biological evaluation of vinylsulfonamide derivatives as highly potent, covalent TEAD autopalmitoylation inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 184(2019):15.