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

doi:10.1021/acs.jmedchem.1c00994

	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
	Jin, Tingting 1; Xu, Lei 2,3; Wang, Peipei 2; Hu, Xiaobei 2,3; Zhang, Runyuan 1; Wu, Zhiqi 3; Du, Wenxin 1; Kan, Weijuan 2; Li, Kun 1; Wang, Chang 2
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2021-10-28
卷号	64 期号:20 页码:15069-15090
ISSN号	0022-2623
DOI	10.1021/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.
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关键词	CHECKPOINT KINASE 1 ; PHASE-I ; PHOSPHORYLATION ; COMBINATION ; GEMCITABINE
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000713412900011
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/298961]
专题	中国科学院上海药物研究所
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.