LSD1 / KDM1A

Class

Small molecule covalent epigenetic (demethylase) inhibitor

Pathway

Histone demethylation (H3K4me1/2, H3K9me1/2) - promotes differentiation of leukemic blasts

LSD1 (lysine-specific demethylase 1), also known as KDM1A, is an enzyme that removes chemical tags called methyl groups from specific sites on histone proteins, the spools around which DNA is wound. These tags are part of the epigenetic system that determines which genes are switched on or off without altering the DNA sequence itself. LSD1 works within larger protein complexes that silence genes, and by erasing an activating mark on histone H3 it helps keep certain genes turned off. In several leukemias, this activity helps trap immature leukemic cells in a self-renewing, undifferentiated state, preventing them from maturing into normal, non-dividing blood cells. Blocking LSD1's catalytic activity, particularly with covalent inhibitors that permanently disable its active site, can release this block and allow leukemic cells to differentiate and lose their capacity to proliferate indefinitely. This approach is broadly relevant in myeloid leukemias and other cancers in which a stalled maturation program, rather than unchecked growth signaling alone, sustains the disease, offering a mechanism distinct from conventional cytotoxic chemotherapy.