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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

文献类型：期刊论文

作者Tong, Lexian1; Song, Pinrao2; Jiang, Kailong3,4; Xu, Lei3,4,5; Jin, Tingting1; Wang, Peipei3,4; Hu, Xiaobei3,4; Fang, Sui4; Gao, Anhui3,4; Zhou, Yubo3,4
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2019-07-01
卷号173页码:44-62
关键词CHK1 kinase inhibitor Selectivity Monotherapy Hematologic malignancies
ISSN号0223-5234
DOI10.1016/j.ejmech.2019.03.062
通讯作者Liu, Tao(Lt601@zju.edu.cn) ; Li, Jia(jli@simm.ac.cn) ; Hu, Yongzhou(huyz@zju.edu.cn)
英文摘要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.
WOS关键词KINASE 1 CHK1 ; STRUCTURE-BASED DESIGN ; BIOLOGICAL EVALUATION ; CHECKPOINT ; POTENT ; OPTIMIZATION
资助项目National Natural Science Foundation of China[81673466] ; National Natural Science Foundation of China[21772174] ; National Natural Science Foundation of China[81172929] ; National Science and Technology Major Project of China[2018ZX09711002-011-015] ; Science and Technology Commission of Shanghai Municipality[16431902200] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020214]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000467888600004
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/289780]  
专题新药研究国家重点实验室
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
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.

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来源：上海药物研究所

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