Enasidenib is an orally available, selective, potent, small molecule inhibitor of mutant isocitrate dehydrogenase 2 (IDH2). Neomorphic mutations in IDH2 are frequently found in both hematologic malignancies and solid tumors and lead to the production of the oncometabolite (R)-2-hydroxyglutarate. Increased levels of (R)-2-hydroxyglutarate cause histone and DNA hypermethylation associated with blocked differentiation and tumorigenesis. In PDX mice transplanted with human IDH2-mutant acute myeloid leukemia cells, enasidenib treatment led to normalization of (R)-2-hydroxyglutarate serum levels, differentiation of leukemic blasts and increased survival. Early clinical data in patients with relapsed/refractory IDH2-mutant acute myeloid leukemia show that enasidenib is well tolerated and induces durable complete remissions as a single agent in about 20% of cases. One notable drug-related adverse effect is differentiation syndrome. On the basis of these results the compound has recently been approved for the treatment of relapsed/refractory IDH2-mutant acute myeloid leukemia in the USA. Although no data are available yet, clinical trials on the treatment of patients with several types of IDH2-mutant solid tumors including gliomas, chondrosarcomas and cholangiocarcinomas are currently being performed.
Keywords: 2-hydroxyglutarate; AG-221; AML; Acute myeloid leukemia; Glioblastoma; Hypermethylation; IDH; Isocitrate dehydrogenase; Ketoglutarate.