Cayman AGI-6780

Isocitrate dehydrogenases (IDHs) are NAD⁺ and NADP⁺-dependent enzymes in the tricarboxylic acid cycle that catalyze oxidative decarboxylation of isocitrate producing α-ketoglutarate (2-OG) and carbon dioxide. IDH1 and IDH2 are mutated in >70% of lower grade gliomas. The most common mutations map to arginine residues in the catalytic pockets of IDH1 (R132) or IDH2 (R140 and R172) and impart new gain of function catalytic activity leading to the NADPH-dependent conversion of 2-OG to 2-hydroxyglutarate (2-HG).^,, AGI-6780 is a potent, selective inhibitor of mutant IDH2 with an IC₅₀ value of 23 nM. It binds allosterically at the dimer interface of mutant IDH2-R140Q, inhibiting 2-HG formation in human glioblastoma U87 and TF-1 cells expressing IDH2-R140Q with IC₅₀ values of 11 and 18 nM, respectively. In primary human acute myelogenous leukemia cells, AGI-6780 suppressed cell growth and induced differentiation of immature blast cells toward macrophage and granulocytic lineages.

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