IDH2

Isocitrate dehydrogenase 1 and 2 (IDH1/2) are key enzymes that function at a crossroads of cellular metabolism, epigenetic regulation, redox states, and DNA repair. IDH1 and IDH2 are highly similar enzymes, forming homodimers and catalyzing the reversible NADP+-dependent oxidative decarboxylation of isocitrate to αKG. NADPH is a key cellular reducing agent required for detoxification processes through reduction of glutathione and thioredoxins and activation of catalase, which are all involved in the protection against the toxicity of reactive oxygen species and oxidative DNA damage. IDH1 is the main NADPH producer in the brain (PMID: 12031902, PMID: 21527585), In hypoxic contexts, IDH1 and IDH2 can also convert αKG to isocitrate. This reductive carboxylation is the reverse of the normal, oxidative decarboxylation. Hypoxia inhibits pyruvate production and therefore TCA cycle flux via upregulation of hypoxia-inducible factor 1α (HIF1α). In such contexts, cells use glutaminolysis to produce citrate, which can be used in fatty acid synthesis (serving as an acetyl-CoA shuttle) or NADPH production (via IDH1 in decarboxylation mode) (PMID: 22101431, PMID: 22106302). DH1/2 mutations decrease the ability of the mutant enzymes to convert isocitrate to αKG3 and that IDH1/2-mutant enzymes inhibit wild-type activity in a dominant-negative manner. Further functional analysis demonstrated that IDH1/2-mutant enzymes gain neomorphic enzymatic activity, converting NADPH and αKG to NADP+ and D-2HG. The resulting d-2HG accumulation competitively inhibits α-ketoglutarate (αKG)-dependent enzymes, causing cellular alterations in the above-mentioned plethora of cellular metabolism, epigenetic regulation, redox states, and DNA repair, all of which may contribute to carcinogenesis which has been extensively reviewed elsewhere (PMID: 21251613). A methylation profile of several human malignancies showed that IDH1/2-mutant tumors display a typical CpG island methylator phenotype characterized by high degree of DNA hypermethylation in CpG-rich domains. Hypermethylation is the dominant feature of IDH1/2-mutant acute myeloid leukemias (AMLs) (PMID: 21130701). IDH1/2 mutations occur in a mutually exclusive manner in ~80% of WHO grade II/III oligodendrogliomas, astrocytomas, and oligoastrocytomas and secondary GBM (PMID: 19228619). IDH1/2 mutations occur in 15% of de novo normal-karyotype AML and 20% of AML that has progressed from myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPN) (PMID: 20538800).

Enasidenib (AG-221) is the first-in-class, orally available, small molecule, selective inhibitor of mIDH2. AG-221 is specific for mutants IDH2R140Q and IDH2R172K, by binding to its allosteric site and stabilizing the homodimer conformation preventing the conformation change required for its catalytic action and the production of the R2HG (PMID: 28193778).