中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 新药研究国家重点实验室
Design, Synthesis, and Biological Evaluation of Orally Bioavailable CHK1 Inhibitors Active against Acute Myeloid Leukemia

文献类型：期刊论文

作者Jin, Tingting2; Wang, Peipei3; Long, Xiubing2; Jiang, Kailong3,4; Song, Pinrao1; Wu, Wenbiao3,4; Xu, Gaoya3; Zhou, Yubo3,4,5; Li, Jia3,4,5; Liu, Tao2
刊名CHEMMEDCHEM
出版日期2021-02-16
页码12
关键词CHK1 inhibitor diaminopyrimidine DNA damage response oral bioavailability
ISSN号1860-7179
DOI10.1002/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
WOS记录号WOS:000618367100001
出版者WILEY-V C H VERLAG GMBH
源URL[http://119.78.100.183/handle/2S10ELR8/295830]  
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.Shanghai Jemincare Pharmaceut Co Ltd, Jemincare Grp Res Inst, 1118 Halei Rd, Shanghai 201203, Peoples R China
2.Zhejiang Univ, Coll Pharmaceut Sci, ZJU ENS Joint Lab Med Chem, Zhejiang Prov Key Lab Anticanc Drug Res, Hangzhou 310058, Peoples R China
3.Chinese Acad Sci, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
4.Univ Chinese Acad Sci, 19 A Yuquan Rd, Beijing 100049, 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.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。