Cited by 207Cancer, Hypoxia, and MetabolismGlioma Diagnosis and TreatmentAcute Myeloid Leukemia Research

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Isocitrate Dehydrogenase Mutation and ( R )-2-Hydroxyglutarate: From Basic Discovery to Therapeutics Development

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Dang, Lenny, Su, Shin-San Michael·2017·Annual Review of Biochemistry

DOI 10.1146/annurev-biochem-061516-044732

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Abstract

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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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
DOI: 10.1146/annurev-biochem-061516-044732
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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Isocitrate Dehydrogenase Mutation and ( R )-2-Hydroxyglutarate: From Basic Discovery to Therapeutics Development

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