discoveryofnovelcbpbromodomaininhibitorsthroughtrfretbasedhighthroughputscreening

doi:10.1038/s41401-019-0256-2

	discoveryofnovelcbpbromodomaininhibitorsthroughtrfretbasedhighthroughputscreening
	Zhang Fengcai 1; Sun Zhongya 2; Liao Liping 3; Zuo Yu 1; Zhang Dan 3; Wang Jun 3; Chen Yantao 3; Xiao Senhao 3; Jiang Hao 3; Lu Tian 3
刊名	actapharmacologicasinica
	2020
卷号	41 期号:2 页码:285
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
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 IC_(50) value of 744.3 nM. This compound bound to CBP BrD with a K_D value of 4.01 μM 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 IC_(50) value of 19.2 μM 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.
语种	英语
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/280715]
专题	中国科学院上海药物研究所
作者单位	1.南昌大学 2.哈尔滨工业大学 3.中国科学院上海药物研究所
推荐引用方式 GB/T 7714	Zhang Fengcai,Sun Zhongya,Liao Liping,et al. discoveryofnovelcbpbromodomaininhibitorsthroughtrfretbasedhighthroughputscreening[J]. actapharmacologicasinica,2020,41(2):285.
APA	Zhang Fengcai.,Sun Zhongya.,Liao Liping.,Zuo Yu.,Zhang Dan.,...&Luo Cheng.(2020).discoveryofnovelcbpbromodomaininhibitorsthroughtrfretbasedhighthroughputscreening.actapharmacologicasinica,41(2),285.
MLA	Zhang Fengcai,et al."discoveryofnovelcbpbromodomaininhibitorsthroughtrfretbasedhighthroughputscreening".actapharmacologicasinica 41.2(2020):285.