Design, synthesis, and biological evaluation of tetrahydroquinolin derivatives as potent inhibitors of CBP bromodomain

doi:10.1016/j.bioorg.2020.103991

	Design, synthesis, and biological evaluation of tetrahydroquinolin derivatives as potent inhibitors of CBP bromodomain
	Chen, Yu 1,2; Bi, Xiaoyang 2,3; Zhang, Fengcai 4; Sun, Zhongya 1,5; Xu, Pan 1,2; Jiang, Hao 1,2; Lu, Wenchao 6; Lu, Tian 1,7; Ding, Hong 1; Zhang, Naixia 8
刊名	BIOORGANIC CHEMISTRY
	2020-08-01
卷号	101 页码:11
关键词	In silico screening Drug design CBP Bromodomain Inhibitor Acute Myeloblastic Leukemia
ISSN号	0045-2068
DOI	10.1016/j.bioorg.2020.103991
通讯作者	Ding, Hong(hding@simm.ac.cn) ; Zhou, Bing(zhoubing@simm.ac.cn) ; Luo, Cheng(cluo@simm.ac.cn)
英文摘要	CREB-binding protein (CBP) is a large multi-domain protein containing a HAT domain catalyzing transacety-lation and a bromodomain responsible for acetylated lysine recognition. CBPs could act as transcription co-activators to regulate gene expression and have been shown to play a significant role in the development and progression of many cancers. Herein, through in silico screening two hit compounds with tetrahydroquinolin methyl carbamate scaffold were discovered, among which DC-CPin7 showed an in vitro inhibitory activity with the TR-FRET IC50 value of 2.5 +/- 0.3 mu M. We obtained a high-resolution co-crystal structure of the CBP bro-modomain in complex with DC-CPin7 to guide following structure-based rational drug design, which yielded over ten DC-CPin7 derivatives with much higher potency, among which DC-CPin711 showed approximately 40-fold potency compared with hit compound DC-CPin7 with an in vitro TR-FRET IC50 value of 63.3 +/- 4.0 nM. Notably, DC-CPin711 showed over 150-fold selectivity against BRD4 bromodomains. Moreover, DC-CPin711 showed micromolar level of anti-leukemia proliferation through G1 phase cell cycle arrest and cell apoptosis. In summary, through a combination of computational and crystal-based structure optimization, DC-CPin711 showed potent in vitro inhibitory activities to CBP bromodomain with a decent selectivity towards BRD4 bro-modomains and good cellular activity to leukemia cells, which could further be applied to related biological and translational studies as well as serve as a lead compound for future development of potent and selective CBP bromodomain inhibitors.
资助项目	National Key R&D Program of China[2017YFB0202600] ; National Natural Science Foundation of China[21820102008] ; National Science and Technology Major Project[2018ZX09711002] ; K.C. Wong Education Foundation ; Science and Technology Commission of Shanghai Municipality[18431907100] ; Science and Technology Commission of Shanghai Municipality[Y811298033] ; Science and Technology Commission of Shanghai Municipality[19XD1404700] ; Personalized Medicines Molecular Signature-based Drug Discovery and Development (Strategic Priority Research Program of the Chinese Academy of Sciences)[XDA12020368]
WOS关键词	C-MYC ; DISCOVERY ; PROTEIN ; COACTIVATOR ; ACETYLATION ; EXPRESSION ; P300 ; GENE
WOS研究方向	Biochemistry & Molecular Biology ; Chemistry
语种	英语
出版者	ACADEMIC PRESS INC ELSEVIER SCIENCE
WOS记录号	WOS:000552622000003
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/292197]
专题	中国科学院上海药物研究所
通讯作者	Ding, Hong; Zhou, Bing; Luo, Cheng
作者单位	1.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 4.Nanchang Univ, Sch Pharm, Nanchang 330006, Jiangxi, Peoples R China 5.Harbin Inst Technol, Sch Life & Technol, Harbin 150001, Peoples R China 6.Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA 7.Nanjing Univ Chinese Med, Jiangsu Key Lab High Technol Res TCM Formulae, 138 Xianlin Rd, Nanjing 210023, Peoples R China 8.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Analyt Chem, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 9.Pilot Natl Lab Marine Sci & Technol Qingdao, Open Studio Druggabil Res Marine Nat Prod, 1 Wenhai Rd, Qingdao 266237, Peoples R China
推荐引用方式 GB/T 7714	Chen, Yu,Bi, Xiaoyang,Zhang, Fengcai,et al. Design, synthesis, and biological evaluation of tetrahydroquinolin derivatives as potent inhibitors of CBP bromodomain[J]. BIOORGANIC CHEMISTRY,2020,101:11.
APA	Chen, Yu.,Bi, Xiaoyang.,Zhang, Fengcai.,Sun, Zhongya.,Xu, Pan.,...&Luo, Cheng.(2020).Design, synthesis, and biological evaluation of tetrahydroquinolin derivatives as potent inhibitors of CBP bromodomain.BIOORGANIC CHEMISTRY,101,11.
MLA	Chen, Yu,et al."Design, synthesis, and biological evaluation of tetrahydroquinolin derivatives as potent inhibitors of CBP bromodomain".BIOORGANIC CHEMISTRY 101(2020):11.