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

doi:10.1016/j.bmc.2021.116422

	Discovery and structure - activity relationship exploration of pyrazolo [1,5-a]pyrimidine derivatives as potent FLT3-ITD inhibitors
	Chen, Yun 1,2; Bai, Gang 3; Li, Yan 3; Ning, Yi 3; Cao, Sufen 2; Zhou, Jinpei 5; Ding, Jian 3; Zhang, Huibin 1; Xie, Hua 3,4; Duan, Wenhu 2
刊名	BIOORGANIC & MEDICINAL CHEMISTRY
	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
DOI	10.1016/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.
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关键词	ACUTE MYELOID-LEUKEMIA ; MUTATIONS
WOS研究方向	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000705197800001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/298430]
专题	中国科学院上海药物研究所
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.