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

文献类型：期刊论文

作者Lv, Kaikai3,4; Chen, Weicong2; Chen, Danqi3; Mou, Jie1; Zhang, Huijie3,4; Fan, Tiantian3,4; Li, Yanlian3; Cao, Danyan3; Wang, Xin3; Chen, Lin3
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2020-09-10
卷号63期号:17页码:9787-9802
ISSN号0022-2623
DOI10.1021/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.
WOS关键词DRUG DISCOVERY ; BROMODOMAIN ; OPTIMIZATION ; POTENT ; 2-THIAZOLIDINONES ; COMBINATION ; GROWTH ; SERIES ; CDK9
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研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000571493400053
出版者AMER CHEMICAL SOC
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.

入库方式： OAI收割

来源：上海药物研究所

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