Identification of novel small-molecule inhibitors targeting menin-MLL interaction, repurposing the antidiarrheal...

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Mixed lineage leukemia (MLL) rearrangements confer a poor prognosis despite advanced treatments.
• Menin is essential for the oncogenic function of MLL fusion proteins.
• Disrupting menin-MLL interactions is a potential therapeutic strategy for MLL leukemia.

Purpose of the Study:

• To identify novel inhibitors of the menin-MLL interaction.
• To repurpose existing drugs and develop new chemical entities targeting MLL leukemia.
• To evaluate the efficacy of novel menin-MLL inhibitors in preclinical models.

Main Methods:

• Shape-based scaffold hopping approach was used to discover menin-MLL inhibitors.
• Loperamide was identified as a mild inhibitor and chemically modified.
• Structure-activity relationship studies were performed on loperamide analogues.
• In vitro assays were used to determine inhibitory concentrations (IC50) and assess cellular effects.

Main Results:

• Loperamide showed mild inhibition of menin-MLL interaction (IC50 = 69 ± 3 μM).
• Three loperamide-based analogues (DC_YM21, DC_YM25, DC_YM26) exhibited significantly improved activity (IC50 values ranging from 0.66 to 0.83 μM).
• DC_YM21 demonstrated potent and selective inhibition of leukemia cell proliferation, induced cell cycle arrest, and promoted differentiation in MLL translocation-bearing cells.

Conclusions:

• Novel chemical scaffolds targeting menin-MLL interactions were discovered.
• Loperamide-based analogues represent promising therapeutic agents for MLL leukemia.
• These findings offer a new avenue for developing targeted therapies for MLL leukemia.