Modulation of Ten-Eleven-Translocation Enzymes as Treatment Option for IDH-mutated Cancer

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Isocitrate dehydrogenases 1, 2 and 3 (IDH1/2/3) are key enzymes of the citrate cycle as they catalyze the oxidative conversion of isocitrate to α-ketoglutarate (αKG). This serves as a co-substrate for αKG-dependent dioxygenases such as the Ten-Eleven-Translocation (TET) enzymes, which play a crucial role in the epigenetic reactivation of decommissioned genes. They catalyze the sequential oxidation of 5-methylcytosine and promote locus-specific DNA demethylation. There is an important correlation between TET and IDH enzymes in the progression of certain tumor diseases. Mutations in IDH1 and IDH2 genes are particularly common in glioblastomas and myelodysplastic syndromes such as acute myeloid leukemia (AML). These mutations lead to neomorphic enzyme activity and massive overproduction of the oncometabolite 2-hydroxyglutarate (2HG), which competes with αKG and inhibits TET enzymes. So far only vitamin C has been described as having an activating effect on TET enzymes. However, the molecular mechanism is not known, a reducing effect on iron ions in the active center of the TETs is discussed. However, other reducing agents have no effect. A possible explanation for this contradiction could be the metabolism of vitamin C. In fact, there is a remarkable structural similarity between αKG, the essential co-factor of TET enzymes, and the vitamin C metabolite 2,3-diketogulonic acid (DKA). Initial preliminary work in silico has already shown that DKA, similar to αKG, fits into the active pocket of TET enzymes and is able to bind functionally. This has already been confirmed with the aid of a cell-free TET enzyme assay and a cell-based test. This finding has so far been completely undescribed. Therefore, the aim of the planned research project is to characterize the exact mechanism of action of vitamin C and its metabolite DKA. Furthermore, therapy options will be developed that can reverse the 2HG-induced inactivation of αKG-dependent dioxygenases. Pharmacodynamic and pharmacokinetic questions will also be answered. For this purpose, genome-wide and gene-specific changes in DNA methylation, DNA hydroxymethylation and further oxidation states are used as evidence of cellular TET activity. In addition, it is of great interest to investigate the possible tumor-inhibiting effect of DKA in the mouse model and to test the possibility of treating acute myeloid leukaemia cells. With the elucidation of the mode of action of DKA, the discovery of new DKA-analog molecule structures will be a further goal of the project. IDH inhibitors for the therapy of AML are already available or are clinically tested. The combination of such inhibitors with new DKA-based analogs would represent a new molecular strategy for the treatment of tumor diseases such as glioblastomas and AML.