Mutant IDH1 and IDH2

Class

Small molecule pan-mutant IDH1/IDH2 inhibitor

Pathway

2-hydroxyglutarate oncometabolite production / TCA cycle and histone-DNA demethylation blockade

Isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) are metabolic enzymes that normally convert isocitrate to alpha-ketoglutarate (α-KG) within the citric acid cycle, the cell's central energy-generating pathway. Certain point mutations recurrent in several cancers change the enzyme's chemistry so that it instead produces an abnormal metabolite, 2-hydroxyglutarate (2-HG), often at very high levels. This oncometabolite structurally resembles α-KG and competitively blocks a family of enzymes that require α-KG as a cofactor, including DNA and histone demethylases. The result is widespread epigenetic hypermethylation that locks cells into an immature, proliferative state, a mechanism implicated in certain leukemias and gliomas. A pan-mutant inhibitor is designed to suppress the altered enzymatic activity of the common disease-associated mutations in both IDH1 and IDH2 with a single agent, rather than requiring separate mutation-specific drugs, and to remain active even when a tumor shifts between different mutant variants over time. By lowering 2-HG production, such agents aim to relieve the epigenetic block and allow abnormal cells to resume normal maturation. This mechanism is broadly relevant wherever IDH mutations drive a block in cellular differentiation.