Point mutations of the isocitrate dehydrogenases IDH1 and IDH2, found in acute myeloid leukaemia (AML), promote a block in cellular differentiation that is due to global DNA hypermethylation. Here, using a high-throughput biochemical screen, Okoye-Okafor et al. identify novel allosteric inhibitors of mutant IDH1. In primary IDH1-mutant AML cells and mouse AML xenograft models, the inhibitors decreased production of the IDH1 metabolite 2-hydroxyglutarate, reduced the percentage of blast cells and stimulated myeloid differentiation, also reversing the aberrant DNA hypermethylation patterns induced by mutant IDH1.
References
Okoye-Okafor, U. C. et al. New IDH1 mutant inhibitors for treatment of acute myeloid leukemia. Nat. Chem. Bio. 11, 878–886 (2015)
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Crunkhorn, S. Novel IDH1 mutant inhibitors identified. Nat Rev Drug Discov 14, 820 (2015). https://doi.org/10.1038/nrd4799
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DOI: https://doi.org/10.1038/nrd4799
