The DOI matches its Crossref record; 109 of the 109 references it cites were found in a registry or an index.
Isocitrate Dehydrogenase Mutation and ( R )-2-Hydroxyglutarate: From Basic Discovery to Therapeutics Development
Open accessAbstract
The identification of heterozygous mutations in the metabolic enzyme isocitrate dehydrogenase (IDH) in subsets of cancers, including secondary glioblastoma, acute myeloid leukemia, intrahepatic cholangiocarcinoma, and chondrosarcomas, led to intense discovery efforts to delineate the mutations’ involvement in carcinogenesis and to develop therapeutics, which we review here. The three IDH isoforms (nicotinamide adenine dinucleotide phosphate–dependent IDH1 and IDH2, and nicotinamide adenine dinucleotide–dependent IDH3) contribute to regulating the circuitry of central metabolism. Several biochemical and genetic observations led to the discovery of the neomorphic production of the oncometabolite (R)-2-hydroxyglutarate (2-HG) by mutant IDH1 and IDH2 (mIDH). Heterozygous mutation of IDH1/2 and accumulation of 2-HG cause profound metabolic and epigenetic dysregulation, including inhibition of normal cellular differentiation, leading to disease. Crystallographic structural studies during the development of compounds targeting mIDH demonstrated common allosteric inhibition by distinct chemotypes. Ongoing clinical trials in patients with mIDH advanced hematologic malignancies have demonstrated compelling clinical proof-of-concept, validating the biology and drug discovery approach.
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“the concentrations at which it accumulates under pathogenic conditions suggests HIF-1α stabilisation and impaired collagen biogenesis may contribute to tumorigenicity126-130.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [128]
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Metadata
- Authors
- Dang, L., & Su, S.-S. M.
- Affiliations
- Agios Pharmaceuticals (United States) (US)
- ORCID
- Dang, Lenny
- Venue
- Annual Review of Biochemistry
- Publisher
- Annual Reviews
- Published
- 2017-06-20
- Volume
- 86
- Issue
- 1
- Pages
- 305-331
- ISSN
- 0066-4154 (ISSN-L)
- 1545-4509
- OpenAlex
- W2556519788
- Cited by
- 204
- References
- 109
- Citations by year
- 2026: 5 · 2025: 15 · 2024: 20 · 2023: 17 · 2022: 22 · 2021: 30 · 2020: 29 · 2019: 23 · 2018: 33 · 2017: 10
- FWCI
- 2.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Annual Review of Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Agios Pharmaceuticals
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- isocitrate dehydrogenase, IDH1 mutation, IDH2 mutation, (R)-2-hydroxyglutarate, oncometabolites, allosteric inhibition, IDH inhibitors, epigenetic dysregulation, secondary glioblastoma, acute myeloid leukemia, cholangiocarcinoma, chondrosarcoma, central carbon metabolism, hematologic malignancies, drug development
- MeSH terms
- Acetamides, Antineoplastic Agents, Benzimidazoles, Enzyme Inhibitors, Glutarates, Humans, Imidazoles, Isocitrate Dehydrogenase, Isoenzymes, Models, Molecular, Mutation, Biomarkers, Tumor, Leukemia, Myeloid, Acute, Gene Expression, Benzeneacetamides, Small Molecule Libraries, Drug Discovery, Translational Research, Biomedical
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