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
  • 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: [email protected].
  • 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: [email protected].
  • 11. Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China. Electronic address: [email protected].
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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