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Design, synthesis and biological evaluation of 2-aminopyrimidine derivatives as potent FLT3 inhibitors

文献类型：期刊论文

作者Lian, Xuanmin8; Gao, Yue7; Li, Xuemei8; Wang, Peipei7; Tong, Lexian6,8; Li, Jia3,4,5,7; Zhou, Yubo4,5; Liu, Tao1,2,8
刊名BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
出版日期2023-11-15
卷号96页码:5
关键词2-aminopyrimidine FLT3 inhibitors MV4-11 FLT3 mutations
ISSN号0960-894X
DOI10.1016/j.bmcl.2023.129519
通讯作者Li, Jia(jli@simm.ac.cn) ; Zhou, Yubo(ybzhou@mail.shcnc.ac.cn) ; Liu, Tao(lt601@zju.edu.cn)
英文摘要Acute myeloid leukemia (AML) is an aggressive cancer, which is characterized by clonal expansion of myeloid progenitors in the bone marrow and peripheral blood. FMS-like tyrosine kinase 3 (FLT3) mutations are the most frequently identified mutations, present in approximately 25-30 % AML patients, making FLT3 inhibitors a crucial treatment option for AML. In this study, we described the design, synthesis and biological evaluation of a series of 2-aminopyrimidine derivatives as potent FLT3 inhibitors. Notably, compound 15 displayed potent kinase inhibitory activities against FLT3 (FLT3-WT IC50 = 7.42 +/- 1.23 nM; FLT3-D835Y IC50 = 9.21 +/- 0.04 nM) and robust antiproliferative activities against MV4-11 cells (IC50 = 0.83 +/- 0.15 nM) and MOLM-13 cells (IC50 = 10.55 +/- 1.70 nM). Compound 15 also possessed potent antiproliferative activities against BaF3 cells carrying various FLT3-TKD and FLT3-ITD-TKD mutations, indicating its potential to overcome on-target resistance caused by FLT3 mutations. In summary, compound 15 showed promising potential for further exploration as a treatment of AML.
WOS关键词RESISTANCE ; CRENOLANIB ; D835
资助项目key project of Zhejiang Provincial Natural Science Foundation of China[LZ21H300001] ; National Natural Science Foundation of China[82273783]
WOS研究方向Pharmacology & Pharmacy ; Chemistry
语种英语
WOS记录号WOS:001095971000001
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/307736]  
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.Zhejiang Univ, Hangzhou Inst Innovat Med, Inst Drug Discovery & Design, Coll Pharmaceut Sci, Hangzhou 310058, Peoples R China
2.Zhejiang Univ, Natl Key Lab Adv Drug Delivery & Release Syst, Hangzhou 310058, Peoples R China
3.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
4.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Guangdong, Peoples R China
5.Chinese Acad Sci, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
6.Zhejiang Univ, Innovat Inst Artificial Intelligence Med, Hangzhou 310018, Zhejiang, Peoples R China
7.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
8.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		 Lian, Xuanmin,Gao, Yue,Li, Xuemei,et al. Design, synthesis and biological evaluation of 2-aminopyrimidine derivatives as potent FLT3 inhibitors[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2023,96:5.
APA Lian, Xuanmin.,Gao, Yue.,Li, Xuemei.,Wang, Peipei.,Tong, Lexian.,...&Liu, Tao.(2023).Design, synthesis and biological evaluation of 2-aminopyrimidine derivatives as potent FLT3 inhibitors.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,96,5.
MLA Lian, Xuanmin,et al."Design, synthesis and biological evaluation of 2-aminopyrimidine derivatives as potent FLT3 inhibitors".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 96(2023):5.

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来源：上海药物研究所

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