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Discovery of 2-Aminopyrimidine Derivatives as Potent Dual FLT3/CHK1 Inhibitors with Significantly Reduced hERG Inhibitory Activities

文献类型：期刊论文

作者Li, Xuemei1; Wang, Peipei2; Wang, Chang3; Jin, Tingting4; Xu, Ran2; Tong, Lexian1,5; Hu, Xiaobei3,6; Shen, Liteng7; Li, Jia2,3,6; Zhou, Yubo2,3,6
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-08-16
页码23
ISSN号0022-2623
DOI10.1021/acs.jmedchem.3c00245
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FLT3 inhibitors as single agents have limited effectsbecause ofacquired and adaptive resistance and the cardiotoxicity related tohuman ether-a-go-go-related gene (hERG) channel blockade further impedessafe drugs to the market. Inhibitors having potential to overcomeresistance and reduce hERG affinity are highly demanded. Here, wereported a dual FLT3/CHK1 inhibitor 18, which displayedpotencies to overcome varying acquired resistance in BaF3 cells withFLT3-TKD and FLT3-ITD-TKD mutations. Moreover, 18 displayedhigh selectivity over c-KIT more than 1700-fold and greatly reducedhERG affinity, with an IC50 value of 58.4 & mu;M. Furthermechanistic studies demonstrated 18 can upregulate p53and abolish the outgrowth of adaptive resistant cells. In the in vivostudies, 18 demonstrated favorable PK profiles and goodsafety, suppressed the tumor growth in the MV-4-11 cell inoculatedmouse xenograft model, and prolonged the survival in the Molm-13 transplantationmodel, supporting its further development.
WOS关键词BACTERIAL TOPOISOMERASE INHIBITORS ; FLT3 ; P53 ; RESISTANCE ; MUTATIONS ; DESIGN
资助项目key project of the Zhejiang Provincial Natural Science Foundation of China[LZ21H300001] ; National Natural Science Foundation of China[82273783] ; National Natural Science Foundation of China[82204179] ; National Natural Science Foundation of China[81673466]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:001050972100001
源URL[http://119.78.100.183/handle/2S10ELR8/306965]  
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, Coll Pharmaceut Sci, ZJU ENS Joint Lab Med Chem, Zhejiang Prov Key Lab Anticanc Drug Res, Hangzhou 310058, Peoples R China
2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Zhejiang Univ, Affiliated Hangzhou Peoples Hosp 1, Sch Med Hangzhou,Key Lab Clin Canc Pharmacol & Tox, Dept Clin Pharm, Hangzhou 310006, Peoples R China
5.Zhejiang Univ, Innovat Inst Artificial Intelligence Med, Hangzhou 310018, Peoples R China
6.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Guangdong, Peoples R China
7.Zhejiang Univ, Hangzhou Inst Innovat Med, Inst Drug Discovery & Design, Coll Pharmaceut Sci, Hangzhou 310058, Peoples R China
推荐引用方式
GB/T 7714		 Li, Xuemei,Wang, Peipei,Wang, Chang,et al. Discovery of 2-Aminopyrimidine Derivatives as Potent Dual FLT3/CHK1 Inhibitors with Significantly Reduced hERG Inhibitory Activities[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023:23.
APA Li, Xuemei.,Wang, Peipei.,Wang, Chang.,Jin, Tingting.,Xu, Ran.,...&Liu, Tao.(2023).Discovery of 2-Aminopyrimidine Derivatives as Potent Dual FLT3/CHK1 Inhibitors with Significantly Reduced hERG Inhibitory Activities.JOURNAL OF MEDICINAL CHEMISTRY,23.
MLA Li, Xuemei,et al."Discovery of 2-Aminopyrimidine Derivatives as Potent Dual FLT3/CHK1 Inhibitors with Significantly Reduced hERG Inhibitory Activities".JOURNAL OF MEDICINAL CHEMISTRY (2023):23.

入库方式： OAI收割

来源：上海药物研究所

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