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Acute myelogenous leukemia (AML)

Isocitrate dehydrogenase 2 (IDH2)

Patient sample and in vitro studies suggest mutant-selective IDH2 inhibitors could help treat patients with IDH2-mutant AML. In in vitro assays, AGI-6780 inhibited mutant IDH2 with nanomolar potency and selectivity over the wild-type enzyme. In primary human AML cells with mutant IDH2, AGI-6780 decreased levels of the (R)-enantiomer of 2-hydroxyglutarate (2-HG), an oncometabolite produced specifically by the mutant enzyme, and increased leukemic cell differentiation compared with vehicle. Next steps include further preclinical development of mutant IDH2 inhibitors in preparation for clinical trials in patients who have IDH2-mutant AML.
Agios Pharmaceuticals Inc. has preclinical programs targeting IDH1 and IDH2 in cancers with mutations in the metabolic enzymes (see Oncometabolite takedown, page 7).

SciBX 6(14); doi:10.1038/scibx.2013.330
Published online April 11, 2013

Patent applications filed; partnered with Celgene Corp.

Wang, F. et al. Science; published online April 4, 2013;
Contact: Katharine E. Yen, Agios Pharmaceuticals Inc., Cambridge, Mass.