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Discovery and structure - activity relationship exploration of pyrazolo [1,5-a]pyrimidine derivatives as potent FLT3-ITD inhibitors

文献类型：期刊论文

作者Chen, Yun1,2; Bai, Gang3; Li, Yan3; Ning, Yi3; Cao, Sufen2; Zhou, Jinpei5; Ding, Jian3; Zhang, Huibin1; Xie, Hua3,4; Duan, Wenhu2
刊名BIOORGANIC & MEDICINAL CHEMISTRY
出版日期2021-10-15
卷号48页码:13
关键词FLT3 FLT3-ITD Acute myeloid leukemia Structure-activity relationships Pyrazolo[1, 5-a]pyrimidine
ISSN号0968-0896
DOI10.1016/j.bmc.2021.116422
通讯作者Zhang, Huibin(zhanghb80@163.com) ; Xie, Hua(hxie@simm.ac.cn) ; Duan, Wenhu(whduan@simm.ac.cn)
英文摘要Internal tandem duplications of FLT3 (FLT3-ITD) occur in approximately 25% of all acute myeloid leukemia (AML) cases and confer a poor prognosis. Optimization of the screening hit 1 from our in-house compound library led to the discovery of a series of pyrazolo[1,5-a]pyrimidine derivatives as potent and selective FLT3-ITD inhibitors. Compounds 17 and 19 displayed potent FLT3-ITD activities both with IC50 values of 0.4 nM and excellent antiproliferative activities against AML cell lines. Especially, compounds 17 and 19 inhibited the quizartinib resistance-conferring mutations, FLT3(D835Y), both with IC50 values of 0.3 nM. Moreover, western blot analysis indicated that compounds 17 and 19 potently inhibited the phosphorylation of FLT3 and attenuated downstream signaling in AML cells. These results indicated that pyrazolo[1,5-a]pyrimidine derivatives could be promising FLT3-ITD inhibitors for the treatment AML.
WOS关键词ACUTE MYELOID-LEUKEMIA ; MUTATIONS
资助项目Institutes for Drug Discovery and Development, Chinese Academy of Sciences[CASIMM0120215010] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; Youth Innovation Promotion Association CAS[2018324]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种英语
WOS记录号WOS:000705197800001
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/298430]  
专题新药研究国家重点实验室
通讯作者Zhang, Huibin; Xie, Hua; Duan, Wenhu
作者单位1.China Pharmaceut Univ, Ctr Drug Discovery, State Key Lab Nat Med, 24 Tongjiaxiang, Nanjing 210009, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Small Mol Drug Res Ctr, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Inst Drug Discovery & Dev, Zhongshan 528400, Peoples R China
5.China Pharmaceut Univ, Dept Med Chem, 24 Tongjiaxiang, Nanjing 210009, Peoples R China
推荐引用方式
GB/T 7714		 Chen, Yun,Bai, Gang,Li, Yan,et al. Discovery and structure - activity relationship exploration of pyrazolo [1,5-a]pyrimidine derivatives as potent FLT3-ITD inhibitors[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2021,48:13.
APA Chen, Yun.,Bai, Gang.,Li, Yan.,Ning, Yi.,Cao, Sufen.,...&Duan, Wenhu.(2021).Discovery and structure - activity relationship exploration of pyrazolo [1,5-a]pyrimidine derivatives as potent FLT3-ITD inhibitors.BIOORGANIC & MEDICINAL CHEMISTRY,48,13.
MLA Chen, Yun,et al."Discovery and structure - activity relationship exploration of pyrazolo [1,5-a]pyrimidine derivatives as potent FLT3-ITD inhibitors".BIOORGANIC & MEDICINAL CHEMISTRY 48(2021):13.

入库方式： OAI收割

来源：上海药物研究所

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