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Discovery and Development of a Potent, Selective, and Orally Bioavailable CHK1 Inhibitor Candidate: 5-((4-((3-Amino-3-methylbutyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)picolinonitrile

文献类型：期刊论文

作者Jin, Tingting1; Xu, Lei2,3; Wang, Peipei2; Hu, Xiaobei2,3; Zhang, Runyuan1; Wu, Zhiqi3; Du, Wenxin1; Kan, Weijuan2; Li, Kun1; Wang, Chang2
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2021-10-28
卷号64期号:20页码:15069-15090
ISSN号0022-2623
DOI10.1021/acs.jmedchem.1c00994
通讯作者Zhou, Yubo(ybzhou@simm.ac.cn) ; Li, Jia(jli@simm.ac.cn) ; Liu, Tao(Lt601@zju.edu.cn)
英文摘要Checkpoint kinase 1 (CHK1) plays an important role in the DNA damage response pathway, being a potential anti-cancer drug target. In this study, we used a strategy for trifluoromethyl substitution to obtain orally bioavailable CHK1 inhibitors to overcome the limitations of lead compound 1, which can only be administered intravenously. After detailed investigation, we identified compound 6c as an oral CHK1 inhibitor, which demonstrated a considerably higher plasma exposure in mice. Compound 6c also showed good kinase selectivity. Moreover, it exhibited a significant antiproliferative effect in MV-4-11 cells singly and a synergistic effect in combination with gemcitabine in HT-29, A549, and RPMI-8226 cells. Additionally, compound 6c could inhibit tumor growth in the MV-4-11 xenograft mouse model. The combination of 6c and gemcitabine exhibited synergistic effect in the HT-29 xenograft mouse model. Thus, compound 6c was found to be a selective and oral potential anticancer CHK1 inhibitor.
WOS关键词CHECKPOINT KINASE 1 ; PHASE-I ; PHOSPHORYLATION ; COMBINATION ; GEMCITABINE
资助项目National Natural Science Foundation of China[21772174] ; National Natural Science Foundation of China[81821005] ; National Natural Science Foundation of China[81673466] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; Science and Technology Commission of Shanghai Municipality[19430750100]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000713412900011
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/298961]  
专题新药研究国家重点实验室
通讯作者Zhou, Yubo; Li, Jia; Liu, Tao
作者单位1.Zhejiang Univ, Coll Pharmaceut Sci, ZJU ENS Joint Lab Med Chem, Zhejiang Prov Key Lab Anticanc Drug Res, Hangzhou 310058, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Guangdong, Peoples R China
推荐引用方式
GB/T 7714		 Jin, Tingting,Xu, Lei,Wang, Peipei,et al. Discovery and Development of a Potent, Selective, and Orally Bioavailable CHK1 Inhibitor Candidate: 5-((4-((3-Amino-3-methylbutyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)picolinonitrile[J]. JOURNAL OF MEDICINAL CHEMISTRY,2021,64(20):15069-15090.
APA Jin, Tingting.,Xu, Lei.,Wang, Peipei.,Hu, Xiaobei.,Zhang, Runyuan.,...&Liu, Tao.(2021).Discovery and Development of a Potent, Selective, and Orally Bioavailable CHK1 Inhibitor Candidate: 5-((4-((3-Amino-3-methylbutyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)picolinonitrile.JOURNAL OF MEDICINAL CHEMISTRY,64(20),15069-15090.
MLA Jin, Tingting,et al."Discovery and Development of a Potent, Selective, and Orally Bioavailable CHK1 Inhibitor Candidate: 5-((4-((3-Amino-3-methylbutyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)picolinonitrile".JOURNAL OF MEDICINAL CHEMISTRY 64.20(2021):15069-15090.

入库方式： OAI收割

来源：上海药物研究所

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