Discovery and preclinical activity of the menin-KMT2A inhibitor ziftomenib in acute leukemia models.

Ziftomenib, a potent menin-KMT2A inhibitor, induces leukemia regression and reduces tumor burden in models of KMT2A-rearranged leukemia, with strong gene downregulation.

• Why it matters: Targeting the menin-KMT2A interaction offers a promising therapeutic approach for aggressive leukemias with specific genetic alterations, addressing a critical unmet need.
• What they did: The study developed and tested ziftomenib, demonstrating its ability to inhibit proliferation, induce differentiation, and downregulate key target genes in leukemia cells and patient samples, including resistant mutants.
• The result: Ziftomenib shows significant preclinical activity, retains efficacy against certain resistant mutants, and has received FDA approval for NPM1-mutated leukemia, supporting its clinical potential.