Inhibitors of mutant IDH1 and IDH2

Somatic mutations in genes encoding isocitrate dehydrogenase isoforms IDH1 and IDH2 have recently been found in 50–80% of human low-grade gliomas, whereas somatic mutations in IDH2 are found in ∼10% of acute myeloid leukemias (AMLs). Scientists now report compounds that selectively inhibit mutant IDH1 and IDH2. Ingo Mellinghoff, Katharine Yen and colleagues report a selective inhibitor (AGI-5198) of mutant R132H IDH1 (Science doi:10.1126/science.1236062, 4 April 2013). The compound inhibited R132H IDH1 but not wild-type IDH1 at half-maximal inhibitory concentration (IC₅₀) = 70 nM. In TS603 glioma cells carrying a heterozygous mutation for R123H IDH1, AGI-5198 decreased colony formation by 40–60%. AGI-5198 also caused 50–60% inhibition of human glioma xenograft growth in mice. Katharine Yen and colleagues identified a small molecule (AGI-6780) that selectively inhibited mutant R140Q IDH2 (IC₅₀ ≤ 20 nM) (Science doi:10.1126/science.1234769, 4 April 2013). They treated primary human AML cells with the mutation for R140Q IDH2 ex vivo, seeing a dose-dependent reduction in the levels of the metabolite 2-hydroxyglutarate and an increase in the numbers of more mature, CD45-positive cells. Their experiments showed that treatment with AGI-6780 reversed growth factor–independent growth and a block in erythroid differentiation seen in human AML cells with mutant R140Q IDH2. Both papers provide evidence that agents targeting mutant IDH1 and IDH2 should be further investigated in the clinic.