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Identification of 2-Aminopyrimidine Derivatives as FLT3 Kinase Inhibitors with High Selectivity over c-KIT

文献类型：期刊论文

作者Tong, Lexian5,6,7; Wang, Peipei4; Li, Xuemei7; Dong, Xiaowu2,3,5; Hu, Xiaobei1,4; Wang, Chang4; Liu, Tao7; Li, Jia1,4; Zhou, Yubo1,4
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-02-24
卷号65期号:4页码:3229-3248
ISSN号0022-2623
DOI10.1021/acs.jmedchem.1c01792
通讯作者Liu, Tao(Lt601@zju.edu.cn) ; Li, Jia(jli@simm.ac.cn) ; Zhou, Yubo(ybzhou@simm.ac.cn)
英文摘要Herein, we report two promising compounds 30 and 36 possessing nanomolar FLT3 inhibitory activities (IC50 = 1.5-7.2 nM), high selectivity over c-KIT (>1000-fold), and excellent anti-AML activity (MV4-11 IC50 = 0.8-3.2 nM). Furthermore, these two compounds efficiently inhibited the growth of multiple mutant BaF3 cells expressing FLT3-ITD, FLT3-D835V/F, FLT3-F691L, FLT3-ITD-F691L, and FLT3-ITD-D835Y. Oral administration of 30 and 36 at 6 mg/kg/d could significantly suppress tumor growth in the MV4-11 cell-inoculated xenograft model, exhibiting tumor growth inhibitory rates of 83.5% and 95.1%, respectively. Importantly, 36 could prolong the mouse survival time in the FLT3-ITD-TKD dual mutation syngeneic mouse model (BaF3-FLT3-ITD-D835Y) at a dose of 6 mg/kg p.o. bid/4W. No clear myelosuppression was observed in the treated group of 36 in the MPO strain of zebrafish, even at 10 mu M. In summary, our data demonstrated that 36 may represent a promising candidate for the treatment of FLT3 mutant AML.
WOS关键词ACUTE MYELOID-LEUKEMIA ; GILTERITINIB ; RESISTANCE ; MUTATIONS ; CHEMOTHERAPY ; DISCOVERY ; POTENT
资助项目Zhejiang Provincial Natural Science Foundation of China[LZ21H300001] ; National Natural Science Foundation of China[81821005] ; 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:000797940600033
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/301349]  
专题新药研究国家重点实验室
通讯作者Liu, Tao; Li, Jia; Zhou, Yubo
作者单位1.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Guangdong, Peoples R China
2.Zhejiang Univ, Canc Ctr, Hangzhou 310058, Peoples R China
3.Zhejiang Univ, Coll Pharmaceut Sci, Hangzhou Inst Innovat Med, Inst Drug Discovery & Design, Hangzhou 310058, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.Zhejiang Univ, Innovat Inst Artificial Intelligence Med, Hangzhou 310018, Peoples R China
6.Zhejiang Univ, Sch Mat Sci & Engn, Hangzhou 310027, Peoples R China
7.Zhejiang Univ, Coll Pharmaceut Sci, ZJU ENS Joint Lab Med Chem, Zhejiang Prov Key Lab Anticanc Drug Res, Hangzhou 310058, Peoples R China
推荐引用方式
GB/T 7714		 Tong, Lexian,Wang, Peipei,Li, Xuemei,et al. Identification of 2-Aminopyrimidine Derivatives as FLT3 Kinase Inhibitors with High Selectivity over c-KIT[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022,65(4):3229-3248.
APA Tong, Lexian.,Wang, Peipei.,Li, Xuemei.,Dong, Xiaowu.,Hu, Xiaobei.,...&Zhou, Yubo.(2022).Identification of 2-Aminopyrimidine Derivatives as FLT3 Kinase Inhibitors with High Selectivity over c-KIT.JOURNAL OF MEDICINAL CHEMISTRY,65(4),3229-3248.
MLA Tong, Lexian,et al."Identification of 2-Aminopyrimidine Derivatives as FLT3 Kinase Inhibitors with High Selectivity over c-KIT".JOURNAL OF MEDICINAL CHEMISTRY 65.4(2022):3229-3248.

入库方式： OAI收割

来源：上海药物研究所

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