2. Academic Validation
  3. Design, synthesis, and evaluation of Menin-targeting compounds for the treatment of acute Myelocytic leukemia (AML)

Design, synthesis, and evaluation of Menin-targeting compounds for the treatment of acute Myelocytic leukemia (AML)

  • Eur J Med Chem. 2025 Jun 12:296:117847. doi: 10.1016/j.ejmech.2025.117847.
Jun Mo 1,  Yuxian Wang 2,  Youlu Pan 3,  Qitao Xiao 1,  Jinyi Zhao 1,  Weijuan Kan 4,  Mengxin Luo 1,  Jingyu Zhang 5,  Yang Lu 1,  Gaoya Xu 4,  Jiangzhou Song 6,  Can Yang 7,  Yunfei Ye 6,  Bo Wang 6,  Xinfei Mao 1,  Huimin Hao 1,  Yubo Zhou 8,  Jinxin Che 1,  Wenhai Huang 3,  Jia Li 2,  Tao Liu 9,  Hanlin Wang 10,  Xiaowu Dong 11
Affiliations

Affiliations

  • 1 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
  • 2 School of Pharmacy, Henan University, Kaifeng, 475004, PR China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China.
  • 3 Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, Zhejiang, 310013, PR China.
  • 4 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
  • 5 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China; Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou First People's Hospital, Cancer Center of Zhejiang University, Hangzhou, 310006, PR China.
  • 6 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China.
  • 7 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, Guangdong, 528400, PR China.
  • 8 University of Chinese Academy of Sciences, Beijing, 100049, PR China.
  • 9 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China. Electronic address: lt601@zju.edu.cn.
  • 10 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China. Electronic address: wanghanlin@simm.ac.cn.
  • 11 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China. Electronic address: dongxw@zju.edu.cn.
PMID: 40532499 DOI: 10.1016/j.ejmech.2025.117847
Abstract

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 μM) 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•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.

Keywords

AML; Anti-proliferation activity; High binding affinity; Menin.

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