Rational Design and Evaluation of 6-(Pyrimidin-2-ylamino)-3,4-dihydroquinoxalin-2(1H)-ones as Polypharmacological Inhibitors of BET and Kinases

doi:10.1021/acs.jmedchem.0c00962

	Rational Design and Evaluation of 6-(Pyrimidin-2-ylamino)-3,4-dihydroquinoxalin-2(1H)-ones as Polypharmacological Inhibitors of BET and Kinases
	Lv, Kaikai 3,4; Chen, Weicong 2; Chen, Danqi 3; Mou, Jie 1; Zhang, Huijie 3,4; Fan, Tiantian 3,4; Li, Yanlian 3; Cao, Danyan 3; Wang, Xin 3; Chen, Lin 3
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2020-09-10
卷号	63 期号:17 页码:9787-9802
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.0c00962
通讯作者	Mou, Jie(100002009710@xzhmu.edu.cn) ; Pei, Dongsheng(dspei@xzhmu.edu.cn) ; Xiong, Bing(bxiong@simm.ac.cn)
英文摘要	Cancer exhibits diverse heterogeneity with a complicated molecular basis that usually harbors genetic and epigenetic abnormality, which poses a big challenge for single-target agents. In the current work, we proposed a hybrid strategy by incorporating pharmacophores that bind to the acetylated lysine binding pocket of BET proteins with a typical kinase hinge binder to generate novel polypharmacological inhibitors of BET and kinases. Through elaborating the core structure of 6-(pyrimidin-2-ylamino)-3,4-dihydroquinoxalin-2(1H)- one, we demonstrated that this rational design can produce high potent inhibitors of CDK9 and BET proteins. In this series, compound 40 was identified as the potential lead compound with balanced activities of BRD4 (IC50 = 12.7 nM) and CDK9 (IC50 = 22.4 nM), as well as good antiproliferative activities on a small cancer cell panel. Together, the current study provided a new method for the discovery of bromodomain and kinase dual inhibitors rather than only being discovered by serendipity.
资助项目	National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China[2018ZX09711002-011-018] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China[2018ZX09711002-004] ; National Natural Science Foundation of China[81330076]
WOS关键词	DRUG DISCOVERY ; BROMODOMAIN ; OPTIMIZATION ; POTENT ; 2-THIAZOLIDINONES ; COMBINATION ; GROWTH ; SERIES ; CDK9
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000571493400053
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/291203]
专题	中国科学院上海药物研究所
通讯作者	Mou, Jie; Pei, Dongsheng; Xiong, Bing
作者单位	1.Xuzhou Med Univ, Sch Pharm, Jiangsu Key Lab New Drug & Clin Pharm, Xuzhou 221006, Jiangsu, Peoples R China 2.Xuzhou Med Univ, Dept Pathol, Xuzhou 221006, Jiangsu, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Lv, Kaikai,Chen, Weicong,Chen, Danqi,et al. Rational Design and Evaluation of 6-(Pyrimidin-2-ylamino)-3,4-dihydroquinoxalin-2(1H)-ones as Polypharmacological Inhibitors of BET and Kinases[J]. JOURNAL OF MEDICINAL CHEMISTRY,2020,63(17):9787-9802.
APA	Lv, Kaikai.,Chen, Weicong.,Chen, Danqi.,Mou, Jie.,Zhang, Huijie.,...&Xiong, Bing.(2020).Rational Design and Evaluation of 6-(Pyrimidin-2-ylamino)-3,4-dihydroquinoxalin-2(1H)-ones as Polypharmacological Inhibitors of BET and Kinases.JOURNAL OF MEDICINAL CHEMISTRY,63(17),9787-9802.
MLA	Lv, Kaikai,et al."Rational Design and Evaluation of 6-(Pyrimidin-2-ylamino)-3,4-dihydroquinoxalin-2(1H)-ones as Polypharmacological Inhibitors of BET and Kinases".JOURNAL OF MEDICINAL CHEMISTRY 63.17(2020):9787-9802.