Discovery of (R)-5-((5-(1-methyl-1H-pyrazol-4-yl)-4-(methylamino) pyrimidin-2-yl)amino)-3-(piperidin-3-yloxy)picolinonitrile, a novel CHK1 inhibitor for hematologic malignancies

doi:10.1016/j.ejmech.2019.03.062

	Discovery of (R)-5-((5-(1-methyl-1H-pyrazol-4-yl)-4-(methylamino) pyrimidin-2-yl)amino)-3-(piperidin-3-yloxy)picolinonitrile, a novel CHK1 inhibitor for hematologic malignancies
	Tong, Lexian 1; Song, Pinrao 2; Jiang, Kailong 3,4; Xu, Lei3,4,5 ; Jin, Tingting 1; Wang, Peipei 3,4; Hu, Xiaobei 3,4; Fang, Sui 4; Gao, Anhui 3,4; Zhou, Yubo 3,4; Liu, Tao 1; Li, Jia3,4,5,6 ; Hu, Yongzhou 1
	2019-07
发表期刊	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (IF:6.0[JCR-2023],6.1[5-Year])
ISSN	0223-5234
卷号	173 页码:44-62
发表状态	已发表
DOI	10.1016/j.ejmech.2019.03.062
摘要	Through virtual screening, we identified the lead compound MCL1020, which exhibited modest CHK1 inhibitory activity. Then a series of 5-(pyrimidin-2-ylamino)picolinonitrile derivatives as CHK1 inhibitors were discovered by further rational optimization. One promising molecule. (R)-17, whose potency was one of the best, had an IC50 of 0.4 nM with remarkable selectivity (>4300-fold CHK1 vs. CHK2). Compound (R)-17 effectively inhibited the growth of malignant hematopathy cell lines especially Z-138 (IC50: 0.013 mu M) and displayed low affinity for hERG (IC50> 40 mu M). Moreover, (R)-17 significantly suppressed the tumor growth in Z-138 cell inoculated xenograft model (20 mg/kg I.V., TGI = 90.29%) as a single agent with body weight unaffected. Taken together, our data demonstrated compound (R)-17 could be a promising drug candidate for the treatment of hematologic malignancies. (C) 2019 Published by Elsevier Masson SAS.
关键词	CHK1 kinase inhibitor Selectivity Monotherapy Hematologic malignancies
收录类别	SCI ; SCIE ; IC
语种	英语
资助项目	Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020214]
WOS研究方向	Pharmacology & Pharmacy
WOS类目	Chemistry, Medicinal
WOS记录号	WOS:000467888600004
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS关键词	KINASE 1 CHK1 ; STRUCTURE-BASED DESIGN ; BIOLOGICAL EVALUATION ; CHECKPOINT ; POTENT ; OPTIMIZATION
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/40902
专题	生命科学与技术学院_博士生生命科学与技术学院_特聘教授组_李佳组
通讯作者	Liu, Tao; Li, Jia; Hu, Yongzhou
作者单位	1.Zhejiang Univ, Coll Pharmaceut Sci, Zhejiang Prov Key Lab Anticanc Drug Res, ZJU ENS Joint Lab Med Chem, Hangzhou 310058, Zhejiang, Peoples R China 2.Shanghai Haini Pharmaceut Co Ltd, Yangtze River Pharmaceut Grp, Shanghai 201318, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China 4.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 5.ShanghaiTech Univ, Shanghai 201210, Peoples R China 6.Pilot Natl Lab Marine Sci & Technol Qingdao, Open Studio Druggabil Res Marine Nat Prod, 1 Wenhai Rd, Qingdao 266237, Shandong, Peoples R China
通讯作者单位	上海科技大学
推荐引用方式 GB/T 7714	Tong, Lexian,Song, Pinrao,Jiang, Kailong,et al. Discovery of (R)-5-((5-(1-methyl-1H-pyrazol-4-yl)-4-(methylamino) pyrimidin-2-yl)amino)-3-(piperidin-3-yloxy)picolinonitrile, a novel CHK1 inhibitor for hematologic malignancies[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2019,173:44-62.
APA	Tong, Lexian.,Song, Pinrao.,Jiang, Kailong.,Xu, Lei.,Jin, Tingting.,...&Hu, Yongzhou.(2019).Discovery of (R)-5-((5-(1-methyl-1H-pyrazol-4-yl)-4-(methylamino) pyrimidin-2-yl)amino)-3-(piperidin-3-yloxy)picolinonitrile, a novel CHK1 inhibitor for hematologic malignancies.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,173,44-62.
MLA	Tong, Lexian,et al."Discovery of (R)-5-((5-(1-methyl-1H-pyrazol-4-yl)-4-(methylamino) pyrimidin-2-yl)amino)-3-(piperidin-3-yloxy)picolinonitrile, a novel CHK1 inhibitor for hematologic malignancies".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 173(2019):44-62.