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Design and development of a series of 4-(piperazin-1-yl)pyrimidines as irreversible menin inhibitors

文献类型：期刊论文

作者Luo, Menglan3,4; Ye, Yunfei1,2; Tang, Lu1,4; Kan, Weijuan2,4; Chen, Lin2,4; Li, Cong2,4; Sheng, Li2,4; Zhou, Yubo1,2; Li, Jia1,4; Xiong, Bing1,4
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-12-15
卷号280页码:20
关键词Menin Covalent inhibitor Antitumor Degradation
ISSN号0223-5234
DOI10.1016/j.ejmech.2024.116918
通讯作者Li, Jia(jli@simm.ac.cn) ; Xiong, Bing(bxiong@simm.ac.cn) ; Wang, Hanlin(wanghanlin@simm.ac.cn) ; Chen, Danqi(dqchen@simm.ac.cn)
英文摘要The interaction between menin and MLL1 protein plays an important role in AML with MLL rearrangement and NPM1 mutation. Blocking the formation of menin-MLL complex can inhibit proliferation and induce differentiation in these cancer subtypes. In development of anticancer drugs, irreversible inhibitors are gaining spotlight as they may have better activities than the reversible analogs. Therefore, we designed and developed a novel series of covalent menin inhibitors. Among these compounds, 37 emerges as a selective and potent inhibitor of MLL fusion protein-expressing leukemic cells. The cellular study indicates 37 has a distinct mechanism of action, in both reducing menin protein levels and downregulating MEN1 transcription. This effect of 37 is not involved in proteasomal degradation, and may directly affect the synthesis of menin protein, which offers a significant advantage in addressing acquired resistance to menin inhibitors. Further study showed that compound 37 has prolonged anti-leukemic action and exhibits promising in vivo efficacy, making it a valuable probe for further menin-MLL interaction studies.
WOS关键词SMALL-MOLECULE INHIBITORS ; MLL INTERACTION ; PROTEIN ; DEMETHYLASE ; MODELS ; GENE
资助项目National Natural Sci-ence Foundation of China[82173658] ; National Natural Sci-ence Foundation of China[82373720] ; Shangdong Laboratory Program[SYS202205]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001332944500001
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/313811]  
专题新药研究国家重点实验室
通讯作者Li, Jia; Xiong, Bing; Wang, Hanlin; Chen, Danqi
作者单位1.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Canc Res Ctr, State Key Lab Drug Res, 501 Haike Rd, Shanghai 201203, Peoples R China
3.Shanghai Univ, Coll Sci, Dept Chem, 99 Shangda Rd, Shanghai 200444, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Luo, Menglan,Ye, Yunfei,Tang, Lu,et al. Design and development of a series of 4-(piperazin-1-yl)pyrimidines as irreversible menin inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2024,280:20.
APA Luo, Menglan.,Ye, Yunfei.,Tang, Lu.,Kan, Weijuan.,Chen, Lin.,...&Chen, Danqi.(2024).Design and development of a series of 4-(piperazin-1-yl)pyrimidines as irreversible menin inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,280,20.
MLA Luo, Menglan,et al."Design and development of a series of 4-(piperazin-1-yl)pyrimidines as irreversible menin inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 280(2024):20.

入库方式： OAI收割

来源：上海药物研究所

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