Isocitrate dehydrogenase is a metabolic enzyme that interconverts isocitrate and alpha-ketoglutarate. The somatic point mutations in IDH1 and IDH2 alter the residues in the enzyme active sites, thereby inducing tumorigenesis. AGI-6780 is a small molecule inhibitor that potently and selectively inhibits the tumor-associated mutant IDH2/R140Q with an IC50 value of 23nM. AGI-6780 also inhibited the formation of oncometabolite (R)-2-hydroxyglutarate (2HG) in TF-1 (IDH2-R140Q) and U87 (IDH2-R140Q) cell lines with IC50 values of 18nM and 11nM, respectively. Pretreatment of AGI-6780 at the doses of 0.2 and 11μM restored the mRNA expression of hemoglobin G1/2 and KLF1 in TF1/R140Q cells in the presence of erythropoietin. In primary patient samples of IDH2/R140Q acute myelogenous leukemia, treatment of 0.5-5μM AGI-6780 dose-dependently decreased the amounts of extracellular and intracellular 2HG. AGI-6780 treatment also increased the number of CD11b-, CD14-, CD15-, and MPO-positive cells in IDH2/R140Q patient samples, but not in IDH2/WT samples. In the presence of 5μM AGI- 6780, unfractionated nucleated bone marrow cells showed a threefold increase in the number of colony- forming units as compared to vehicle-treated cells[3].
作用机制
AGI-6780 inhibits IDH2/R140Q via binding at the dimer interface in an allosteric manner[3].
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