IDH2

Class

Small molecule IDH2 (isocitrate dehydrogenase 2) inhibitor

Pathway

Mutant-IDH2 2-hydroxyglutarate oncometabolite production / epigenetic dysregulation

Isocitrate dehydrogenase 2 (IDH2) is a mitochondrial enzyme that normally converts isocitrate into alpha-ketoglutarate, a metabolite used by numerous cellular enzymes as a required cofactor. In certain cancers, particularly acute myeloid leukemia, point mutations in IDH2 change its chemistry so that it no longer performs this normal reaction efficiently but instead produces an abnormal metabolite called 2-hydroxyglutarate (2-HG). Because 2-HG closely resembles alpha-ketoglutarate, it competitively blocks a family of enzymes that depend on alpha-ketoglutarate to modify DNA and histone proteins. The result is widespread epigenetic dysregulation that locks blood progenitor cells in an immature, self-renewing state rather than allowing them to mature into functional blood cells, a hallmark of leukemia. Small-molecule IDH2 inhibitors are designed to bind the mutant enzyme selectively and suppress 2-HG production, thereby removing the block on normal differentiation programs. This mechanism matters broadly wherever recurrent IDH2 mutations drive a cancer's biology, since restoring epigenetic balance can allow malignant cells to differentiate rather than simply killing them outright, a distinct therapeutic rationale from conventional cytotoxic approaches. The approach is most established in hematologic malignancies but reflects a general principle applicable to other IDH-mutant tumors.