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Design, Synthesis, and Biological Evaluation of 2-Aminothiazole Derivatives as Novel Checkpoint Kinase 1 (CHK1) Inhibitors

文献类型：期刊论文

作者Deng, Minjie2; Wang, Peipei3; Long, Xiubing4; Xu, Gaoya3; Wang, Chang6; Li, Jia1,3,6; Zhou, Yubo3,5,6; Liu, Tao2,7
刊名CHEMMEDCHEM
出版日期2023-02-02
页码19
关键词2-aminothiazole CHK1 inhibitors antiproliferation hematologic malignancies biological activity
ISSN号1860-7179
DOI10.1002/cmdc.202200664
通讯作者Li, Jia(jli@simm.ac.cn) ; Zhou, Yubo(ybzhou@simm.ac.cn) ; Liu, Tao(lt601@zju.edu.cn)
英文摘要A series of 2-aminothiazole derivatives were designed, synthesized on the basis of bioisosterism strategy and evaluated for their CHK1 inhibitory activity. Most of them exhibited potent CHK1 inhibition, and excellent antiproliferative activity against MV-4-11 and Z-138 cell lines. Systematic structure-activity relationship (SAR) efforts led to the discovery of a promising compound 8 n, which showed potent CHK1 inhibitory activity with IC50 value of 4.25 +/- 0.10 nM, excellent antiproliferative activity against MV-4-11 and Z-138 cells with IC50 value of 42.10 +/- 5.77 nM and 24.16 +/- 6.67 nM, respectively, as well as moderate oral exposure (AUC((0-t))=1076.25 h center dot ng/mL) in mice. Additionally, treatment of MV-4-11 cells with compound 8 n for 2 h led to robust inhibition of CHK1 autophosphorylation on serine 296. Furthermore, kinase selectivity assay revealed that 8 n displayed acceptable selectivity toward 15 kinases. These results demonstrated that compound 8 n may be a promising potential anticancer agent for further development.
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:000922553100001
出版者WILEY-V C H VERLAG GMBH
源URL[http://119.78.100.183/handle/2S10ELR8/303379]  
专题新药研究国家重点实验室
通讯作者Li, Jia; Zhou, Yubo; Liu, Tao
作者单位1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China
2.Zhejiang Univ, Coll Pharmaceut Sci, ENS Joint Lab Med Chem, ZJU, Hangzhou 310058, Peoples R China
3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
4.Wuxi Apptec Co Ltd, 288 Fute Zhong Rd, Shanghai 200131, Peoples R China
5.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
7.Zhejiang Univ, Hangzhou Inst Innovat Med, Inst Drug Discovery & Design, Hangzhou 310058, Peoples R China
推荐引用方式
GB/T 7714		 Deng, Minjie,Wang, Peipei,Long, Xiubing,et al. Design, Synthesis, and Biological Evaluation of 2-Aminothiazole Derivatives as Novel Checkpoint Kinase 1 (CHK1) Inhibitors[J]. CHEMMEDCHEM,2023:19.
APA Deng, Minjie.,Wang, Peipei.,Long, Xiubing.,Xu, Gaoya.,Wang, Chang.,...&Liu, Tao.(2023).Design, Synthesis, and Biological Evaluation of 2-Aminothiazole Derivatives as Novel Checkpoint Kinase 1 (CHK1) Inhibitors.CHEMMEDCHEM,19.
MLA Deng, Minjie,et al."Design, Synthesis, and Biological Evaluation of 2-Aminothiazole Derivatives as Novel Checkpoint Kinase 1 (CHK1) Inhibitors".CHEMMEDCHEM (2023):19.

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来源：上海药物研究所

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