Targeting LSD1 with INCB059872: A Promising Therapeutic Approach for Human and Murine AML

Acute myeloid leukemia (AML) is a malignancy marked by the abnormal proliferation of hematopoietic stem cells due to a disruption in their differentiation process. This condition is often linked to genetic mutations that alter the epigenetic state, leading to the maintenance of cancerous traits and a block in myeloid maturation. Lysine-specific demethylase 1 (LSD1), which removes methyl groups from certain histone residues, is implicated in sustaining these cancerous programs and hindering differentiation in AML.

The article presents INCB059872, a newly developed inhibitor of LSD1 that forms a covalent bond with the enzyme's FAD cofactor. This compound has been shown to effectively inhibit the growth of AML cells and to promote their differentiation, as evidenced by the increased expression of CD86 and CD11b, markers indicative of myeloid differentiation. Both in vitro and in vivo studies have demonstrated the drug's ability to induce differentiation and reduce tumor growth in human AML cell lines and primary cells, as well as in xenograft models.

In a murine model that closely mirrors human AML, INCB059872 was found to extend the survival of mice with MLL-AF9-induced leukemia. The compound induced differentiation in murine blast cells, decreased the number of blast colonies, and improved hematological parameters, bringing them closer to those of healthy mice. The study also highlighted that optimal therapeutic effects could be achieved with both daily and every-other-day dosing schedules due to the drug's long-lasting effects.

Overall, the research underscores the significance of LSD1 in the pathophysiology of AML and suggests that INCB059872 holds promise as a novel therapeutic agent for this disease. The findings were shared at the 107th Annual Meeting of the American Association for Cancer Research.