Mutant IDH / 2-hydroxyglutarate
A single mutation in a metabolic enzyme (IDH1 or IDH2) makes cells pour out a molecule they should never make, 2-hydroxyglutarate. It jams the machinery that erases chemical marks on DNA and histones, so blood and brain cells get stuck before they mature. Pills that block the mutant enzyme let them mature again.
Overview
Wild-type IDH1 (cytoplasm) and IDH2 (mitochondria) convert isocitrate to α-ketoglutarate. Hotspot mutations (IDH1 R132, IDH2 R140/R172) give the enzyme a new activity: reducing α-ketoglutarate to the oncometabolite (R)-2-hydroxyglutarate, which reaches millimolar levels. 2-HG competitively inhibits α-ketoglutarate-dependent dioxygenases: the TET family of DNA demethylases (producing the CpG island hypermethylator phenotype, G-CIMP, in glioma and a TET2-like phenotype in AML), the JmjC histone demethylases and prolyl hydroxylases. The result is a block in differentiation rather than fast proliferation, which is why IDH-mutant gliomas are slow-growing and why the drugs work by differentiation. Mutant-selective inhibitors ivosidenib (IDH1), olutasidenib (IDH1), enasidenib (IDH2) and the brain-penetrant dual inhibitor vorasidenib are approved: ivosidenib in AML, cholangiocarcinoma and MDS; vorasidenib for grade 2 IDH-mutant glioma after the INDIGO trial. Differentiation syndrome is the class toxicity; resistance arises through second-site IDH mutations and switching from IDH1 to IDH2 (or back).
In one picture
A factory machine (IDH) that is supposed to make one part is bent so it makes a rogue part (2-HG) that gums up the erasers (TET, histone demethylases) which normally wipe old instructions off the blueprint. Cells cannot read the 'grow up' instructions and stay immature. The inhibitors straighten the machine; the erasers work again and the cells mature.
Diagram
top- Ivosidenib (IDH1) for relapsed AML, first-line AML with azacitidine (AGILE), IDH1-mutant cholangiocarcinoma and MDS
- Olutasidenib (IDH1) and enasidenib (IDH2) for relapsed or refractory AML
- Vorasidenib (dual IDH1/2, brain-penetrant) for residual or recurrent grade 2 IDH-mutant astrocytoma and oligodendroglioma (INDIGO)
- Differentiation syndrome is the class toxicity; steroids and hydroxyurea manage it
- Combination with venetoclax and azacitidine, and with PARP inhibitors (2-HG induces a homologous-recombination defect), under study
Pages like this
not linked directly; found by shared links- TermDifferentiation syndrome
Shares Enasidenib, Olutasidenib, Ivosidenib, IDH1 / IDH2.
- TrialClarIDHy
Shares Ivosidenib, IDH1 / IDH2, Biliary tract cancer (cholangiocarcinoma).
- CompanyServier
Shares Vorasidenib, Ivosidenib, Biliary tract cancer (cholangiocarcinoma), Glioma & glioblastoma.
- TrialAGILE
Shares Ivosidenib, IDH1 / IDH2, Acute myeloid leukaemia.
- CompanyRigel Pharmaceuticals
Shares Olutasidenib, Acute myeloid leukaemia.
- Key paperINDIGO: vorasidenib, the first targeted drug for IDH-mutant low-grade glioma
Shares Vorasidenib, IDH1 / IDH2, Glioma & glioblastoma.
- PathwayGlutamine addiction
Shares Vorasidenib, Ivosidenib, IDH1 / IDH2, Glioma & glioblastoma.
- TechnologyEpigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)
Shares Enasidenib, Olutasidenib, Vorasidenib, Ivosidenib.