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A metabolic enzyme whose mutant form produces a molecule that scrambles how genes are read; blocking it slows brain tumours and leukaemias.
IDH1 and IDH2 are metabolic enzymes whose mutant forms produce the oncometabolite 2-hydroxyglutarate, which inhibits TET and histone demethylases and scrambles how genes are read; inhibitors of the mutant enzyme lower 2-HG and let cells differentiate. Ivosidenib (IDH1) and enasidenib (IDH2) are approved in AML, ivosidenib in cholangiocarcinoma, and vorasidenib (Voranigo, dual IDH1/2) in grade 2 IDH-mutant glioma after INDIGO (2024), the first targeted therapy for low-grade glioma. IDH mutations occur in roughly 70 to 80 percent of grade 2 to 3 gliomas but under 10 percent of primary glioblastoma, in 15 to 20 percent of AML and 10 to 20 percent of intrahepatic cholangiocarcinoma, and in chondrosarcoma. Differentiation syndrome in AML and the durability of glioma control are open questions. Blocking a mutant metabolic enzyme slows brain tumours and leukaemias.
In plain words · A metabolic enzyme whose mutant form produces a molecule that scrambles how genes are read; blocking it slows brain tumours and leukaemias.
A metabolic enzyme whose mutant form produces a molecule that scrambles how genes are read; blocking it slows brain tumours and leukaemias.
Neomorphic enzyme activity; 2-HG inhibits TET and histone demethylases.
8 products aim at IDH1 / IDH2: small molecules and other agents. Inhibitors are shaped to fit the enzyme's active site so the reaction the cancer relies on stops.
Tumour-specific alteration: 2 of 2 label readouts filed under it measure a sequence variant (IDH1 R132 mutation, IDH2 mutation (R140 and R172)) absent from normal cells. HPA IDH1: RNA tissue enhanced (liver 501 nTPM); high antibody staining in 10 normal tissues; highest cancer staining prostate cancer (6 of 11 high). HPA IDH2: RNA group enriched (heart muscle 462 nTPM, skeletal muscle 1,220 nTPM, tongue 1,504 nTPM); high antibody staining in 24 normal tissues; highest cancer staining colorectal cancer (7 of 12 high). Distribution: 3 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Brain and spinal cord tumours (all types), Leukaemia, Biliary tract cancer (all types)); approvals of single-target medicines aimed at it also list Nasal cavity and paranasal sinus cancers (including esthesioneuroblastoma), not counted; Open Targets associates it with 8 specific cancer types at or above 0.5 (acute myeloid leukemia, Ollier disease, glioblastoma, cholangiocarcinoma, glioma, Maffucci syndrome and more). (Rule 3 of scripts/fetch-target-specificity.ts.)
Sources: IDH1 R132 mutation label threshold; IDH2 mutation (R140 and R172) label threshold; Human Protein Atlas IDH1 tissue; Human Protein Atlas IDH2 tissue; Open Targets ENSG00000138413 associations; Open Targets ENSG00000182054 associations
What a pathology or genomic report can say about this target, each with the thresholds approvals use.
Cell lines and mouse models for this target →
Neomorphic enzyme activity; 2-HG inhibits TET and histone demethylases.
RNA: tissue enhanced (liver 501 nTPM), detected in all normal tissues.
Medium: Adipose tissue, Appendix, Breast, Duodenum, Kidney, Liver, Pancreas, Rectum.
Medium only: breast cancer, cervical cancer, colorectal cancer, glioma.
HPA IDH1 tissue · HPA IDH1 pathology · HPA protein class: FDA approved drug targets
RNA: group enriched (heart muscle 462 nTPM, skeletal muscle 1,220 nTPM, tongue 1,504 nTPM), detected in all normal tissues.
Medium: Adipose tissue, Breast, Cerebral cortex, Endometrium, Gallbladder, Hippocampus, Lung, Oral mucosa.
Medium only: renal cancer, thyroid cancer.
HPA IDH2 tissue · HPA IDH2 pathology · HPA protein class: FDA approved drug targets
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
| 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) | |
| Prostate cancer | 0.5-1% | Hotspot mutation defining a methylator subtype | cBioPortal: 5 of 494, 1.0%, in prad_tcga_pan_can_atlas_2018 (2 R132C, 1 R132G, 1 R132H); 9 of 1,013, 0.9%, in prad_p1000; 14 of 2,260, 0.6%, in prostate_msk_2024; 3 of 477, 0.6%, in prad_cpcg_2017. The TCGA taxonomy put it at 1% of 333 primary tumours and showed the IDH1-mutant subset carried a methylator phenotype (Cancer Genome Atlas Research Network 2015). | cBioPortal (TCGA) |
| Gallbladder cancer | 0.4% | Mutation | IDH1 mutation in 1 of 244 samples, 0.4%, and no IDH2 mutation in cBioPortal gbc_mskcc_2022; 2 of 103 and 1 of 103 in gbc_msk_2018. | cBioPortal (TCGA) |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Enasidenib is the IDH2 counterpart of ivosidenib, approved in the US for relapsed disease but never approved in Europe after it failed to extend survival in a confirmatory trial.
HMPL-306 is an experimental small-molecule drug from Hutchmed in phase 3 trials for acute myeloid leukaemia, aimed at IDH1 / IDH2.
The first drug to block a mutant metabolic enzyme in cancer. With azacitidine it tripled survival in IDH1-mutated AML that could not take intensive chemotherapy.
Olutasidenib is a second IDH1 inhibitor for relapsed AML, with a higher response rate in its pivotal cohort than ivosidenib had in its own.
The first FDA-approved gene panel that could match one biopsy to several different lung cancer drugs at once.
Safusidenib is an experimental small molecule inhibitor from Nuvation Bio in phase 3 trials for glioma & glioblastoma, aimed at IDH1 / IDH2.
TQB3454 is an experimental small-molecule drug from Chia Tai Tianqing Pharmaceutical in phase 3 trials for biliary tract cancer, aimed at IDH1 / IDH2.
The first targeted therapy for low-grade brain tumours, delaying the need for radiation and chemotherapy by years.
Young adults with a grade 2 IDH-mutant glioma who have had surgery can now take a daily tablet that slows or reverses tumour growth and defers radiotherapy and chemotherapy, both of which carry long-term cognitive costs, by years. It confirms that the IDH mutation is a driver that can be targeted, not just a marker. Whether it improves survival or cognition over the long term, and whether it helps in higher-grade or previously treated tumours, is unknown.
Biliary tumours are often diagnosed on tiny biopsies or brushings, so a blood-based panel that detects HER2 amplification and other targets in half of patients is a practical route to testing, with tissue confirmation where the blood is uninformative.
Sinonasal undifferentiated carcinoma can be confirmed by IDH2 testing or mutant-IDH immunohistochemistry rather than diagnosed by exclusion, and IDH2 inhibitors such as enasidenib became rational candidates for trials.
The clearest early head-to-head of the three biliary sites on one platform: for gallbladder cancer it made HER2 the target to test for and showed that IDH and FGFR inhibitors would rarely apply.
The reference classification of prostate cancer as it presents, and the source of the two numbers that drive most molecular treatment decisions in the disease: a quarter with a PI3K or MAPK lesion, which is the rationale for capivasertib in PTEN-deficient disease, and a fifth with DNA repair inactivation, which is the rationale for PARP inhibitors.
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.
Shares Eytan M. Stein, Differentiation syndrome, Epigenetic progenitor theory: cancer without a first mutation, Epigenetic therapy roadmap: loosening silenced genes → mutation-specific enzymes → editing the epigenome and the tag epigenetic.
Shares Group trials by broken mechanism, not by organ or single mutation, Epigenetic progenitor theory: cancer without a first mutation, Epigenetic therapy roadmap: loosening silenced genes → mutation-specific enzymes → editing the epigenome, Epigenetic reprogramming and the tag epigenetic.
Shares Epigenetic therapy roadmap: loosening silenced genes → mutation-specific enzymes → editing the epigenome and the tag epigenetic.
Shares Biliary cancer: utility of next-generation sequencing for clinical management, Glutamine addiction, Gallbladder cancer and the tag driver.
Shares Intrahepatic, perihilar, distal and gallbladder cancer, Circulating tumor DNA profiling of advanced biliary tract cancers, Biliary cancer: utility of next-generation sequencing for clinical management, National Cancer Centre Singapore and the tag driver.
Shares Timothy J. Ley, Epigenetic reprogramming, Acute myeloid leukaemia and the tag driver.
Shares Group trials by broken mechanism, not by organ or single mutation, Epigenetic reprogramming, Acute myeloid leukaemia and the tag driver.
Shares Circulating tumor DNA profiling of advanced biliary tract cancers, Oncomine Dx Target Test, SAFIR-ABC10, Glioma (KEGG map) and the tag driver.