agi-6780 and alpha-hydroxyglutarate

A number of human cancers harbor somatic point mutations in the genes encoding isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2). These mutations alter residues in the enzyme active sites and confer a gain-of-function in cancer cells, resulting in the accumulation and secretion of the oncometabolite (R)-2-hydroxyglutarate (2HG). We developed a small molecule, AGI-6780, that potently and selectively inhibits the tumor-associated mutant IDH2/R140Q. A crystal structure of AGI-6780 complexed with IDH2/R140Q revealed that the inhibitor binds in an allosteric manner at the dimer interface. The results of steady-state enzymology analysis were consistent with allostery and slow-tight binding by AGI-6780. Treatment with AGI-6780 induced differentiation of TF-1 erythroleukemia and primary human acute myelogenous leukemia cells in vitro. These data provide proof-of-concept that inhibitors targeting mutant IDH2/R140Q could have potential applications as a differentiation therapy for cancer.

Topics: Allosteric Site; Antineoplastic Agents; Catalytic Domain; Cell Line, Tumor; Cell Proliferation; Cells, Cultured; Crystallography, X-Ray; Enzyme Inhibitors; Erythropoiesis; Gene Expression Regulation, Leukemic; Glutarates; Hematopoiesis; Humans; Isocitrate Dehydrogenase; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid, Acute; Molecular Targeted Therapy; Mutant Proteins; Phenylurea Compounds; Point Mutation; Protein Multimerization; Protein Structure, Secondary; Small Molecule Libraries; Sulfonamides