agi-5198 and Leukemia--Myeloid--Acute

The identification of heterozygous mutations in the metabolic enzyme isocitrate dehydrogenase (IDH) in subsets of cancers, including secondary glioblastoma, acute myeloid leukemia, intrahepatic cholangiocarcinoma, and chondrosarcomas, led to intense discovery efforts to delineate the mutations' involvement in carcinogenesis and to develop therapeutics, which we review here. The three IDH isoforms (nicotinamide adenine dinucleotide phosphate-dependent IDH1 and IDH2, and nicotinamide adenine dinucleotide-dependent IDH3) contribute to regulating the circuitry of central metabolism. Several biochemical and genetic observations led to the discovery of the neomorphic production of the oncometabolite (R)-2-hydroxyglutarate (2-HG) by mutant IDH1 and IDH2 (mIDH). Heterozygous mutation of IDH1/2 and accumulation of 2-HG cause profound metabolic and epigenetic dysregulation, including inhibition of normal cellular differentiation, leading to disease. Crystallographic structural studies during the development of compounds targeting mIDH demonstrated common allosteric inhibition by distinct chemotypes. Ongoing clinical trials in patients with mIDH advanced hematologic malignancies have demonstrated compelling clinical proof-of-concept, validating the biology and drug discovery approach.

Topics: Acetamides; Antineoplastic Agents; Benzeneacetamides; Benzimidazoles; Biomarkers, Tumor; Drug Discovery; Enzyme Inhibitors; Gene Expression; Glutarates; Humans; Imidazoles; Isocitrate Dehydrogenase; Isoenzymes; Leukemia, Myeloid, Acute; Models, Molecular; Mutation; Small Molecule Libraries; Translational Research, Biomedical

Topics: Animals; Benzeneacetamides; Cell Differentiation; Cell Transformation, Neoplastic; Enzyme Inhibitors; Glioma; Glutarates; Hematopoiesis; Humans; Imidazoles; Isocitrate Dehydrogenase; Leukemia; Leukemia, Myeloid, Acute; Phenylurea Compounds; Procollagen-Proline Dioxygenase; Sulfonamides