Targeting epigenetic machinery: Emerging novel allosteric inhibitors

doi:10.1016/j.pharmthera.2019.107406

	Targeting epigenetic machinery: Emerging novel allosteric inhibitors
	Ye, Fei 1,2,4; Huang, Jing 3,5; Wang, Hongbo 1,4; Luo, Cheng 3,5,6; Zhao, Kehao 1,4
刊名	PHARMACOLOGY & THERAPEUTICS
	2019-12-01
卷号	204 页码:24
关键词	Epigenetics PRC2 MLL complex SWI/SNF DNMT1 allosteric inhibitors
ISSN号	0163-7258
DOI	10.1016/j.pharmthera.2019.107406
通讯作者	Wang, Hongbo(hongbowangyt@gmail.com) ; Luo, Cheng(cluo@mail.shcnc.ac.cn) ; Zhao, Kehao(kehaozhao@gmail.com)
英文摘要	Epigenetics has emerged as an extremely exciting fast-growing area of biomedical research in post genome era. Epigenetic dysfunction is tightly related with various diseases such as cancer and aging related degeneration, potentiating epigenetics modulators as important therapeutics targets. Indeed, inhibitors of histone deacetylase and DNA methyltransferase have been approved for treating blood tumor malignancies, whereas inhibitors of histone methyltransferase and histone acetyl-lysine recognizer bromodomain are in clinical stage. However, it remains a great challenge to discover potent and selective inhibitors by targeting catalytic site, as the same subfamily of epigenetic enzymes often share high sequence identity and very conserved catalytic core pocket. It is well known that epigenetic modifications are usually carried out by multi-protein complexes, and activation of catalytic subunit is often tightly regulated by other interactive protein component, especially in disease conditions. Therefore, it is not unusual that epigenetic complex machinery may exhibit allosteric regulation site induced by protein-protein interactions. Targeting allosteric site emerges as a compelling alternative strategy to develop epigenetic drugs with enhanced druggability and pharmacological profiles. In this review, we highlight recent progress in the development of allosteric inhibitors for epigenetic complexes through targeting protein-protein interactions. We also summarized the status of clinical applications of those inhibitors. Finally, we provide perspectives of future novel allosteric epigenetic machinery modulators emerging from otherwise undruggable single protein target. (C) 2019 The Authors. Published by Elsevier Inc.
资助项目	National Natural Science Foundation of China[21877095] ; 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[81728020] ; Key Research Project of Shandong Province[2017GSF18177] ; Natural Science Foundation of Shangdong Province[ZR2018LH025] ; Key Research Project of Yantai[2019XDHZ102] ; National Science and Technology Major Project[2018ZX09711002] ; Science and Technology Commission of Shanghai Municipality[9XD1404700] ; K. C. Wong Education Foundation ; Taishan Scholarship
WOS关键词	SMALL-MOLECULE INHIBITORS ; PROTEIN-PROTEIN INTERACTION ; STRUCTURE-BASED DESIGN ; MENIN-MLL INTERACTION ; REPRESSIVE COMPLEX 2 ; CELL SELF-RENEWAL ; H3K4 METHYLTRANSFERASE ACTIVITY ; STRUCTURE-BASED OPTIMIZATION ; DNA METHYLATION PATTERNS ; ACETYLATED HISTONE H4
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000498385300008
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/282097]
专题	中国科学院上海药物研究所
通讯作者	Wang, Hongbo; Luo, Cheng; Zhao, Kehao
作者单位	1.Yantai Univ, Collaborat Innovat Ctr Adv Drug Delivery Syst & B, Yantai 264005, Peoples R China 2.Zhejiang Sci Tech Univ, Coll Life Sci & Med, Hangzhou 310018, Zhejiang, Peoples R China 3.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China 4.Yantai Univ, Key Lab Mol Pharmacol & Drug Evaluat, Sch Pharm, Minist Educ, Yantai, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China 6.Guizhou Univ Tradit Chinese Med, Dept Pharm, South Dong Qing Rd, Guizhou 550025, Peoples R China
推荐引用方式 GB/T 7714	Ye, Fei,Huang, Jing,Wang, Hongbo,et al. Targeting epigenetic machinery: Emerging novel allosteric inhibitors[J]. PHARMACOLOGY & THERAPEUTICS,2019,204:24.
APA	Ye, Fei,Huang, Jing,Wang, Hongbo,Luo, Cheng,&Zhao, Kehao.(2019).Targeting epigenetic machinery: Emerging novel allosteric inhibitors.PHARMACOLOGY & THERAPEUTICS,204,24.
MLA	Ye, Fei,et al."Targeting epigenetic machinery: Emerging novel allosteric inhibitors".PHARMACOLOGY & THERAPEUTICS 204(2019):24.