Design, synthesis, and evaluation of Menin-targeting compounds for the treatment of acute Myelocytic leukemia (AML)
文献类型：期刊论文
| 作者 | Mo, Jun7; Wang, Yuxian4,5,6; Pan, Youlu3; Xiao, Qitao7; Zhao, Jinyi7; Kan, Weijuan5; Luo, Mengxin7; Zhang, Jingyu2,7; Lu, Yang7; Xu, Gaoya5 |
| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2025-10-15 |
| 卷号 | 296页码:17 |
| 关键词 | Menin High binding affinity Anti-proliferation activity AML |
| ISSN号 | 0223-5234 |
| DOI | 10.1016/j.ejmech.2025.117847 |
| 通讯作者 | Liu, Tao(lt601@zju.edu.cn) ; Wang, Hanlin(wanghanlin@simm.ac.cn) ; Dong, Xiaowu(dongxw@zju.edu.cn) |
| 英文摘要 | Menin has emerged as a highly promising therapeutic target for various cancers. Currently, several compounds featuring diverse scaffolds designed to target the Menin-MLL interaction are undergoing clinical studies for the treatment of related indications. BMF-219, a promising inhibitor in Phase 2 clinical trials (NCT05153330), forms a stable and irreversible covalent bond with Menin. Its unique mechanism enables it to overcome the limitations of conventional Menin-MLL inhibitors, thereby enhancing pan-tumor cytotoxicity. However, no comprehensive structural studies based on BMF-219 have been reported to date. Therefore, given its potential, further structural optimization of BMF-219 is essential to better understand its characteristics and enhance its therapeutic efficacy. Herein, compound MJ-26 was developed with superior degradation activity, demonstrating high binding affinity (KD: 0.56 mu M) and anti-proliferative activities. Additionally, MJ-26 hydrochloride demonstrated acceptable pharmacokinetic (PK) profiles (T1/2: 6.48 +/- 1.17 h, Cmax: 1784.67 +/- 236.05 ng/mL, and AUC0-t: 8442.72 +/- 1560.41 ng/mL center dot h). Finally, in vivo activity evaluation demonstrated that MJ-26 hydrochloride also displayed anti-tumor efficacy in the MV-4-11 mouse xenograft model. These findings may offer valuable insights and guidance for the development of Menin-targeting compounds for the treatment of hematologic malignancies. |
| WOS关键词 | MLL INTERACTION ; INHIBITOR ; PROTEIN |
| 资助项目 | National Natural Sci-ence Foundation of China[22477111] ; National Natural Sci-ence Foundation of China[82404655] ; Key R & D Program of Zhejiang Province[2023C03111] ; Shanghai Science and Technology Development Funds[24YF2755300] ; Shandong Laboratory Program[SYS202205] ; Taishan Scholars Program[tstp0648] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[CASIMM0120225001] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM0320231005] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001513789900002 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/318648]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Liu, Tao; Wang, Hanlin; Dong, Xiaowu |
| 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, Hangzhou First Peoples Hosp, Key Lab Clin Canc Pharmacol & Toxicol Res Zhejiang, Canc Ctr, Hangzhou 310006, Peoples R China 3.Hangzhou Med Coll, Ctr Safety Evaluat & Res, Hangzhou 310013, Zhejiang, Peoples R China 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China 6.Henan Univ, Sch Pharm, Kaifeng 475004, 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 | Mo, Jun,Wang, Yuxian,Pan, Youlu,et al. Design, synthesis, and evaluation of Menin-targeting compounds for the treatment of acute Myelocytic leukemia (AML)[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2025,296:17. |
| APA | Mo, Jun.,Wang, Yuxian.,Pan, Youlu.,Xiao, Qitao.,Zhao, Jinyi.,...&Dong, Xiaowu.(2025).Design, synthesis, and evaluation of Menin-targeting compounds for the treatment of acute Myelocytic leukemia (AML).EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,296,17. |
| MLA | Mo, Jun,et al."Design, synthesis, and evaluation of Menin-targeting compounds for the treatment of acute Myelocytic leukemia (AML)".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 296(2025):17. |
入库方式： OAI收割
来源：上海药物研究所
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