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d-2-hydroxyglutarate diethyl ester
- Development stage
- Preclinical
- Lead developer
- Texas Tech University Health Sciences Center
- Modality
- Small Molecules
- Administration
- Intraperitoneal
01
Overview
d-2-hydroxyglutarate diethyl ester is a cell-permeable derivative of the oncometabolite D-2-hydroxyglutarate (D-2HG), which accumulates in cancers harboring mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2). As a structural analog of alpha-ketoglutarate (α-KG), D-2HG acts as a competitive inhibitor of α-KG-dependent dioxygenases, including the TET family of DNA demethylases and various histone demethylases. This inhibition leads to a hypermethylated epigenetic state and the transcriptional silencing of genes such as the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT). By mimicking the effects of IDH mutations, d-2-hydroxyglutarate diethyl ester has been investigated as a potential therapeutic strategy to sensitize high-grade gliomas and glioblastomas to alkylating agents like temozolomide. The diethyl ester formulation is specifically used to enhance cellular uptake compared to the polar parent molecule. It was primarily developed and studied by researchers at the Texas Tech University Health Sciences Center.
- Other names
- D-2HG diethyl esterD2HG diethyl esterD 2HG diethyl esterdiethyl (2R)-2-hydroxypentanedioatediethyl D-2-hydroxyglutarate
02
Targets
2-OGDD (Alpha-ketoglutarate-dependent dioxygenase)TET2 (Methylcytosine dioxygenase TET2)TET1 (Methylcytosine dioxygenase TET1)KDM5 (Lysine-specific demethylase 5 family)TET3 (Tet methylcytosine dioxygenase 3)AGT (O6-methylguanine-DNA methyltransferase)
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