IDH1 / IDH2
A metabolic enzyme whose mutant form produces a molecule that scrambles how genes are read; blocking it slows brain tumours and leukaemias. This dossier gathers the 4 products (4 approved), 3 trials, 4 pathways and 0 resistance routes in the corpus that involve it, with external identifiers so it can be joined to UniProt, ChEMBL, Open Targets and the rest of biology.
Biology
Neomorphic enzyme activity; 2-HG inhibits TET and histone demethylases.
- Low-grade glioma (~80%)
- AML (~20%)
- Cholangiocarcinoma (~15%)
- Chondrosarcoma
Elsewhere: identifiers and databases
Built from HGNC, Ensembl, UniProt and ChEMBL idsHow common it is, by cancer
Full matrix →| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Glioma & glioblastoma | 70-80% | IDH1/2 mutation in grade 2-3 glioma | <10% in primary glioblastoma | cBioPortal (TCGA) |
| Acute myeloid leukaemia | 15-20% | IDH1 or IDH2 mutation | cBioPortal (TCGA) | |
| Biliary tract cancer | 10-20% | IDH1 mutation (intrahepatic) | cBioPortal (TCGA) |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Mutation hotspots and which drugs address them
| Residue | Kind | How common | What it does | Addressed by | Defeats | Source |
|---|---|---|---|---|---|---|
| R132H 132 | Other | About 90% of IDH1 mutations in glioma | Neomorphic: the mutant enzyme makes 2-hydroxyglutarate. R132H is the glioma allele; R132C is more common in AML and cholangiocarcinoma. | — | Yan et al., NEJM 2009 | |
| R132C / R132G / R132S / R132L 132 | Other | not sourced | Non-H alleles enriched in AML, cholangiocarcinoma and chondrosarcoma; covered by the same inhibitors. | — | COSMIC: IDH1 | |
| IDH2 R140Q / R172K (paired gene) 140 | Other | not sourced | Shown for reference at the equivalent IDH1 coordinate: enasidenib covers IDH2; vorasidenib covers both enzymes in glioma. | — | COSMIC: IDH2 |
Frequencies are quoted from the source on each row; a blank means no figure was sourced, not that it is rare. Domain boundaries are approximate. Sources for the map: Cancer Hotspots (MSK) · COSMIC: IDH1.
Products by modality and phase
Browse products →| Modality | Approved |
|---|---|
| Small molecule 4 |
Trials
Evidence ranking →| Trial | Phase | Status | Setting | Result | Products |
|---|---|---|---|---|---|
| INDIGO NCT04164901 | 3 | Positive | Residual or recurrent grade 2 IDH-mutant astrocytoma or oligodendroglioma after surgery, no prior RT/chemo: vorasidenib vs placebo | PFS 27.7 vs 11.1 months, HR 0.39. | |
| AGILE NCT03173248 | 3 | Positive | Newly diagnosed IDH1-mutated AML unfit for intensive chemotherapy: ivosidenib + azacitidine vs placebo + azacitidine | OS 24.0 vs 7.9 months; HR 0.44. | |
| ClarIDHy NCT02989857 | 3 | Positive | Previously treated IDH1-mutant cholangiocarcinoma: ivosidenib vs placebo | PFS HR 0.37; crossover-adjusted OS HR 0.49. |
Resistance routes that involve this target
Unaddressed routes →The resistance atlas has no route that names this target.
Pathways where it is a node
Pathway-to-drug matrix →- Cancer metabolismNode: Mutant IDH → 2-HG · 1 druggable nodes
Cancer cells rewire how they eat. They burn glucose inefficiently but fast (the Warburg effect), gorge on glutamine and fats, and build the nucleotides and lipids needed to divide. This is why the FDG PET scan works, and why metabolism is a drug target.
Which nodes have drugs → - Epigenetic reprogrammingNode: DNA methylation (DNMT, TET2, IDH/2-HG) · 3 druggable nodes
Cancer changes not just its genes but how they are read: chemical tags on DNA and histones silence guardians and awaken growth programmes. Unlike mutations, these changes are reversible, which is the hope behind epigenetic drugs.
Which nodes have drugs → - Glutamine addictionNode: IDH → 2-HG / reductive · 4 druggable nodes
After glucose, glutamine is the tumour's favourite food. It feeds the energy cycle, donates nitrogen for making DNA letters, and makes the antioxidant glutathione. MYC- and KRAS-driven cancers eat so much of it that they starve the T cells next door.
Which nodes have drugs → - Mutant IDH / 2-hydroxyglutarateNode: Mutant IDH1 / IDH2 (R132, R140, R172) · 1 druggable nodes
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.
Which nodes have drugs →
Companion diagnostics and assays
Assay registry →| Assay | Platform | Cut-off | Gates |
|---|---|---|---|
| FoundationOne CDx Foundation Medicine (Roche) · FDA CDx 2017 | NGS tissue | Per companion claim: EGFR, ALK, BRAF V600, ERBB2 amplification, KRAS wild-type, BRCA1/2 and HRR genes, PIK3CA, MET exon 14, RET, FGFR2 fusions, IDH1, NTRK fusions; MSI-high; TMB at least 10 mutations per megabase | |
| Abbott RealTime IDH1 Abbott Molecular · FDA CDx 2018 | PCR | Mutation detected (ivosidenib, AML) | |
| Abbott RealTime IDH2 Abbott Molecular · FDA CDx 2017 | PCR | Mutation detected (enasidenib, AML) |
Preclinical models
All models →| Cell line | Identifiers | Why it is used |
|---|---|---|
| HT-1080 | CVCL_0317 · ACH-000054 | Fibrosarcoma, IDH1 R132C; the most used endogenous mutant-IDH1 line. |
| BT142 | CVCL_D718 | Glioma, IDH1 R132H (hemizygous); one of few IDH-mutant glioma lines that grows. |
| TS603 | CVCL_A5HW | Glioma, IDH1 R132H neurosphere culture. |
| SW1353 | CVCL_0543 · ACH-000418 | Chondrosarcoma, IDH2 R172S. |
| RBE | CVCL_4896 · ACH-001856 | Cholangiocarcinoma, IDH1 R132S. |
| SNU-1079 | CVCL_5008 · ACH-000209 | Cholangiocarcinoma, IDH1 R132C. |
- Idh2 R172K; Kras G12D liver (Albumin-Cre driven) Saha et al., Nature 2014
IDH-mutant gliomas are notoriously hard to culture and lose the mutation or growth in vitro; most work uses engineered lines or slow-growing PDX (e.g. the Mayo GBM panel).
Open questions
All open questions →- 01
When should vorasidenib be started in IDH-mutant glioma, and can it delay or replace radiotherapy and chemotherapy?
clinicalclinicWhy unresolved. INDIGO enrolled grade 2 patients after surgery only; whether IDH inhibition helps after radiotherapy, in grade 3 disease, or as a way to defer radiotherapy-related cognitive harm is untested.
What would answer it. Trials in grade 3 and post-radiotherapy settings, and a comparison of early vorasidenib versus standard chemoradiotherapy with cognitive endpoints.
Source: INDIGO, NEJM 2023
Ideas and companies
Key papers and the live literature
Preprints →- INDIGO: vorasidenib, the first targeted drug for IDH-mutant low-grade glioma · New England Journal of Medicine 2023
Query for this target: (TITLE:"IDH1 / IDH2" OR ABSTRACT:"IDH1 / IDH2" OR TITLE:"IDH1" OR ABSTRACT:"IDH1" OR TITLE:"IDH2" OR ABSTRACT:"IDH2") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about IDH1 / IDH2, not a curated reading list.
Export
The dossier as machine-readable JSON: identifiers from HGNC, Ensembl, UniProt and ChEMBL, products with status, trials, pathways, hotspots, open questions and assays. The full entity record is in the open API at /api/v1/entities/idh.json. Licence CC BY 4.0.