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

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.