Design, Synthesis, and Biological Evaluation of Orally Bioavailable CHK1 Inhibitors Active against Acute Myeloid Leukemia

doi:10.1002/cmdc.202000882

	Design, Synthesis, and Biological Evaluation of Orally Bioavailable CHK1 Inhibitors Active against Acute Myeloid Leukemia
	Jin, Tingting 1; Wang, Peipei 2; Long, Xiubing 1; Jiang, Kailong 2,3; Song, Pinrao 4; Wu, Wenbiao 2,3; Xu, Gaoya 2; Zhou, Yubo 2,3,5; Li, Jia 2,3,5; Liu, Tao 1
刊名	CHEMMEDCHEM
	2021-02-16
页码	12
关键词	CHK1 inhibitor diaminopyrimidine DNA damage response oral bioavailability
ISSN号	1860-7179
DOI	10.1002/cmdc.202000882
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) is a central component in DNA damage response and has emerged as a target for antitumor therapeutics. Herein, we describe the design, synthesis, and biological evaluation of a novel series of potent diaminopyrimidine CHK1 inhibitors. The compounds exhibited moderate to potent CHK1 inhibition and could suppress the proliferation of malignant hematological cell lines. The optimized compound 13 had a CHK1 IC50 value of 7.73 +/- 0.74 nM, and MV-4-11 cells were sensitive to it (IC50=0.035 +/- 0.007 mu M). Furthermore, compound 13 was metabolically stable in mouse liver microsomes in vitro and displayed moderate oral bioavailability in vivo. Moreover, treatment of MV-4-11 cells with compound 13 for 2 h led to robust inhibition of CHK1 autophosphorylation on serine 296. Based on these biochemical results, we consider compound 13 to be a promising CHK1 inhibitor and potential anticancer therapeutic agent.
资助项目	National Natural Science Foundation of China[21772174] ; National Natural Science Foundation of China[81673466]
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	WILEY-V C H VERLAG GMBH
WOS记录号	WOS:000618367100001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/295830]
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, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, 19 A Yuquan Rd, Beijing 100049, Peoples R China 4.Shanghai Jemincare Pharmaceut Co Ltd, Jemincare Grp Res Inst, 1118 Halei Rd, Shanghai 201203, Peoples R China 5.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Inst Drug Discovery Innovat, Zhongshan 528400, Peoples R China
推荐引用方式 GB/T 7714	Jin, Tingting,Wang, Peipei,Long, Xiubing,et al. Design, Synthesis, and Biological Evaluation of Orally Bioavailable CHK1 Inhibitors Active against Acute Myeloid Leukemia[J]. CHEMMEDCHEM,2021:12.
APA	Jin, Tingting.,Wang, Peipei.,Long, Xiubing.,Jiang, Kailong.,Song, Pinrao.,...&Liu, Tao.(2021).Design, Synthesis, and Biological Evaluation of Orally Bioavailable CHK1 Inhibitors Active against Acute Myeloid Leukemia.CHEMMEDCHEM,12.
MLA	Jin, Tingting,et al."Design, Synthesis, and Biological Evaluation of Orally Bioavailable CHK1 Inhibitors Active against Acute Myeloid Leukemia".CHEMMEDCHEM (2021):12.