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Discovery and optimization of Menin-MLL inhibitors targeting acute myeloid leukemia

文献类型：期刊论文

作者Xiao, Qitao2; Wang, Yuxian1,6,7; Shen, Zheyuan2; Mo, Jun2; Li, Cong6,7; Jiang, Rongkuan2; Zhang, Jingyu2; Zhou, Yubo5,6,7; Dong, Xiaowu2; Wang, Hanlin6,7
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2026-04-05
卷号307页码:15
关键词MLL-R AML Menin inhibitor thieno[2 d ]pyrimidine Machine learning
ISSN号0223-5234
DOI10.1016/j.ejmech.2026.118641
通讯作者Dong, Xiaowu(dongxw@zju.edu.cn) ; Wang, Hanlin(wanghanlin@simm.ac.cn) ; Liu, Tao(lt601@zju.edu.cn)
英文摘要A machine learning-guided strategy, which integrated unsupervised structural clustering to identify diverse scaffolds for molecular hybridization followed by synergistic QSAR and molecular docking screening, identified lead compound 7. Guided by this lead, a series of thieno[2,3-d]pyrimidine derivatives were developed as menin inhibitors through several rounds of rational structural optimization. Among them, compound A13 exhibited potent anti-proliferative activity against MV4-11 cells (0.379 +/- 0.182 mu M). Besides, mechanistic studies confirmed A13 disrupts menin-MLL interactions, induces cell differentiation, and selectively inhibits MLLrearranged (MV4-11, MOLM-13) and DNMT3A/NPM1-mutated (OCI-AML3) leukemia cells. The stable binding mode of A13 with menin was further elucidated by molecular dynamics simulations. Moreover, A13 exhibited favorable oral pharmacokinetic properties, characterized by rapid absorption (Tmax =1.67 h) and high plasma exposure (AUC0-t =2241 ng h/mL), demonstrating its potential as a promising candidate for further preclinical development against MLL-rearranged AML.
WOS关键词PROTEIN ; DESIGN
资助项目National Natural Science Foundation of China[22477111] ; National Natural Science Foundation of China[82404655] ; Key R&D Program of Zhejiang Province[2023C03111] ; Key R&D Program of Zhejiang Province[2024C03058] ; Shanghai Science and Technology Development Funds[24YF2755300]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001689109000001
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/322993]  
专题中国科学院上海药物研究所
通讯作者Dong, Xiaowu; Wang, Hanlin; Liu, Tao
作者单位1.Henan Univ, Sch Pharm, Kaifeng 475004, Peoples R China
2.Zhejiang Univ, Inst Drug Discovery & Design, Coll Pharmaceut Sci, Zijingang Campus, Hangzhou 310058, Peoples R China
3.Zhejiang Univ, Inst Drug Discovery & Design, Coll Pharmaceut Sci, Zijingang Campus, Hangzhou 310058, Peoples R China
4.Zhejiang Univ, Hangzhou Inst Innovat Med, Inst Drug Discovery & Design, Hangzhou 310058, Peoples R China
5.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
6.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Xiao, Qitao,Wang, Yuxian,Shen, Zheyuan,et al. Discovery and optimization of Menin-MLL inhibitors targeting acute myeloid leukemia[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2026,307:15.
APA Xiao, Qitao.,Wang, Yuxian.,Shen, Zheyuan.,Mo, Jun.,Li, Cong.,...&Liu, Tao.(2026).Discovery and optimization of Menin-MLL inhibitors targeting acute myeloid leukemia.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,307,15.
MLA Xiao, Qitao,et al."Discovery and optimization of Menin-MLL inhibitors targeting acute myeloid leukemia".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 307(2026):15.

入库方式： OAI收割

来源：上海药物研究所

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