Targeting KMT2A-Altered and NPM1-Mutant Leukemia: The Therapeutic Potential of Menin-KMT2A Inhibitor JNJ-75276617

Acute myeloid leukemia (AML) is marked by a block in cell differentiation, leading to a buildup of immature cells. Therapies that can cause these cells to mature, especially if they also prevent cell growth, are seen as promising for treating acute leukemias. The fusion proteins of histone-lysine N-methyltransferase-2A (KMT2A), also known as Mixed lineage leukemia 1 (MLL1), require interaction with the nuclear protein menin to transcribe genes that can cause leukemia. Disrupting the connection between menin and KMT2A has been shown to promote cell maturation and stop the progression of AML with KMT2A rearrangements and B-cell acute lymphoblastic leukemia (B-ALL) in animals. This disruption also inhibits leukemias caused by mutations in nucleophosmin 1 (NPM1), which are common in AML and rely on the expression of genes targeted by menin-KMT2A, such as MEIS1.

A new drug, JNJ-75276617, is being tested as a way to block the interaction between menin and KMT2A. This drug is taken orally and is a potent and selective inhibitor of the interaction between KMT2A and menin. It has a strong affinity for the KMT2A binding site on menin in humans, mice, and dogs and shows high biochemical potency across different species. In cells with KMT2A rearrangements or mutations in cytoplasmic NPM1, JNJ-75276617 prevents the menin-KMT2A complex from binding to the DNA of genes that it targets, reducing the expression of these genes. The drug also increases the expression of genes that promote cell differentiation.

JNJ-75276617 has shown strong antiproliferative effects on various AML cell lines and patient samples with KMT2A changes or NPM1 mutations. It is significantly more selective for these cells than for normal cells. The drug has induced the expression of differentiation markers and cell death in AML cell lines. In mice, it has caused bone marrow cells to differentiate into a type of white blood cell. In animal models of AML, JNJ-75276617 has reduced the amount of leukemia and increased survival time. The drug has good oral bioavailability and pharmacokinetics in animals.

The results suggest that JNJ-75276617 is a potent and selective inhibitor of the menin-KMT2A interaction. It has shown significant activity against AML/ALL cell lines and primary AML cells and can be used to measure how well the drug is reaching its target. This supports the start of a clinical trial to test JNJ-75276617 as a single treatment for patients with relapsed or refractory acute leukemia who have changes in KMT2A or NPM1.