Discovery of novel CBP bromodomain inhibitors through TR-FRET-based high-throughput screening

doi:10.1038/s41401-019-0256-2

	Discovery of novel CBP bromodomain inhibitors through TR-FRET-based high-throughput screening
	Zhang, Feng-cai 6; Sun, Zhong-ya 1,2; Liao, Li-ping 2,4; Zuo, Yu 2,6; Zhang, Dan 2,3; Wang, Jun 2,5; Chen, Yan-tao 2,4; Xiao, Sen-hao 2,4; Jiang, Hao 2,4; Lu, Tian 2,5
刊名	ACTA PHARMACOLOGICA SINICA
	2020-02-01
卷号	41 期号:2 页码:286-292
关键词	CBP bromodomain small-molecule inhibitor high-throughput screening TR-FRET molecular modeling human leukemia MV4-11 cells
ISSN号	1671-4083
DOI	10.1038/s41401-019-0256-2
通讯作者	Liu, Chuan-peng(liucp74@hotmail.com) ; Luo, Cheng(cluo@simm.ac.cn)
英文摘要	The cAMP-responsive element binding protein (CREB) binding protein (CBP) and adenoviral E1A-binding protein (P300) are two closely related multifunctional transcriptional coactivators. Both proteins contain a bromodomain (BrD) adjacent to the histone acetyl transferase (HAT) catalytic domain, which serves as a promising drug target for cancers and immune system disorders. Several potent and selective small-molecule inhibitors targeting CBP BrD have been reported, but thus far small-molecule inhibitors targeting BrD outside of the BrD and extraterminal domain (BET) family are especially lacking. Here, we established and optimized a TR-FRET-based high-throughput screening platform for the CBP BrD and acetylated H4 peptide. Through an HTS assay against an in-house chemical library containing 20 000 compounds, compound DC_CP20 was discovered as a novel CBP BrD inhibitor with an IC50 value of 744.3 nM. This compound bound to CBP BrD with a K-D value of 4.01 mu M in the surface plasmon resonance assay. Molecular modeling revealed that DC_CP20 occupied the Kac-binding region firmly through hydrogen bonding with the conserved residue N1168. At the celluslar level, DC_CP20 dose-dependently inhibited the proliferation of human leukemia MV4-11 cells with an IC50 value of 19.2 mu M and markedly downregulated the expression of the c-Myc in the cells. Taken together, the discovery of CBP BrD inhibitor DC_CP20 provides a novel chemical scaffold for further medicinal chemistry optimization and a potential chemical probe for CBP-related biological function research. In addition, this inhibitor may serve as a promising therapeutic strategy for MLL leukemia by targeting CBP BrD protein.
资助项目	National Natural Science Foundation of China[91853205] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81430084] ; KC Wong Education Foundation ; Chinese Academy of Sciences[XDA12020353] ; Chinese Academy of Sciences[CASIMM0120184015] ; China Postdoctoral Science Foundation[2017M621571] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; Science and Technology Commission of Shanghai Municipality[19XD1404700] ; National Science & Technology Major Project of China[2018ZX09711002]
WOS关键词	CBP/P300 BROMODOMAIN ; C-MYC ; ACETYLATION ; OPTIMIZATION ; RECOGNITION ; DOCKING ; COACTIVATOR ; PROGRESS ; BINDING ; GROWTH
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000510769500016
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/281728]
专题	中国科学院上海药物研究所
通讯作者	Liu, Chuan-peng; Luo, Cheng
作者单位	1.Harbin Inst Technol, Sch Life & Technol, Harbin 150001, Peoples R China 2.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, Key Lab Receptor Res, Shanghai 201203, Peoples R China 3.Guizhou Univ Tradit Chinese Med, Dept Pharm, Guiyang 550025, Peoples R China 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 5.Nanjing Univ Chinese Med, Jiangsu Key Lab High Technol Res TCM Formulae, Nanjing 210023, Peoples R China 6.Nanchang Univ, Sch Pharm, Nanchang 330006, Jiangxi, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Feng-cai,Sun, Zhong-ya,Liao, Li-ping,et al. Discovery of novel CBP bromodomain inhibitors through TR-FRET-based high-throughput screening[J]. ACTA PHARMACOLOGICA SINICA,2020,41(2):286-292.
APA	Zhang, Feng-cai.,Sun, Zhong-ya.,Liao, Li-ping.,Zuo, Yu.,Zhang, Dan.,...&Luo, Cheng.(2020).Discovery of novel CBP bromodomain inhibitors through TR-FRET-based high-throughput screening.ACTA PHARMACOLOGICA SINICA,41(2),286-292.
MLA	Zhang, Feng-cai,et al."Discovery of novel CBP bromodomain inhibitors through TR-FRET-based high-throughput screening".ACTA PHARMACOLOGICA SINICA 41.2(2020):286-292.