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

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Ziftomenib is an orally bioavailable, highly potent, and selective small molecule inhibitor of the menin-KMT2A interaction.
It shows profound inhibition of proliferation, reduces clonogenic potential, and induces differentiation in leukemia cells and primary patient samples.
Ziftomenib downregulates menin-KMT2A target genes such as MEIS1, HOXA9, and HOXB2.
In xenograft and patient-derived xenograft models, ziftomenib induces leukemia regression or reduces leukemia burden.
Ziftomenib retains anti-leukemic activity against certain MEN1 mutants (T349M, G331R) but shows resistance to others (M327I, G331D).
Crystal structures reveal a similar binding mode of ziftomenib to menin wild-type and mutant variants (T349M, G331R).
FDA-approved for adult patients with NPM1-mutated acute myeloid leukemia, ziftomenib is under clinical evaluation for leukemias with NPM1 or KMT2A alterations.

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