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Isocitrate dehydrogenase 1

Isocitrate dehydrogenase 1 (IDH1) is a NADP+-dependent enzyme encoded by the IDH1 gene on chromosome 2q34 that catalyzes the reversible oxidative decarboxylation of isocitrate to α-ketoglutarate (2-oxoglutarate) in the cytosol and peroxisomes, thereby generating NADPH to support cellular redox balance, antioxidant defense, and anabolic processes such as lipid and cholesterol biosynthesis.^[1] The protein functions as a homodimer consisting of 414 amino acids and is ubiquitously expressed across human tissues, with particularly high levels in the adrenal gland (RPKM 116.0) and liver (RPKM 110.2).^[1] In physiology, IDH1 plays a key role in the tricarboxylic acid (TCA) cycle by facilitating the interconversion of metabolites, contributing to NADPH production for reductive carboxylation pathways that enable citrate synthesis in the absence of mitochondrial function.^[2] Disruptions in this pathway, particularly through somatic mutations, have profound implications in oncology; heterozygous point mutations at residue R132 (most commonly R132H) occur in over 70% of World Health Organization grade II and III gliomas and approximately 80% of secondary glioblastomas, as well as 5–20% of acute myeloid leukemias (AML).^[3]^[2] These gain-of-function mutations alter the enzyme's active site, redirecting α-ketoglutarate to produce the oncometabolite D-2-hydroxyglutarate (D-2-HG), which competitively inhibits α-ketoglutarate-dependent dioxygenases involved in DNA and histone demethylation, leading to global DNA hypermethylation (glioma CpG island methylator phenotype, or G-CIMP), epigenetic dysregulation, and impaired cellular differentiation.^[4] As a result, IDH1 mutations are mutually exclusive with other driver alterations, confer a favorable prognosis in gliomas (e.g., 93% vs. 51% 5-year survival for IDH-mutant vs. wild-type grade II astrocytomas),^[5] and serve as diagnostic biomarkers via immunohistochemistry or sequencing. Targeted therapies, including mutant-specific IDH1 inhibitors like ivosidenib (FDA-approved for IDH1-mutant AML as of 2018) and vorasidenib (FDA-approved for IDH1/2-mutant grade 2 gliomas as of August 2024), have demonstrated clinical efficacy in reducing 2-HG levels and restoring normal cellular metabolism in IDH1-mutant AML and, in clinical trials, advanced gliomas.^[6]^[7]^[8]

Gene and Expression

Genomic Location

The IDH1 gene is situated on the long (q) arm of human chromosome 2 at cytogenetic band 2q34, with precise genomic coordinates spanning from 208,236,227 to 208,255,071 on the reverse strand according to the GRCh38.p14 assembly.^[1] This positions the gene within a region of approximately 18.8 kb, encompassing the full span from the transcription start site to the polyadenylation site.^[9] The gene is organized into 10 exons in its canonical transcript (ENST00000345146.7), which encodes the primary protein isoform of 414 amino acids, with the initial two exons containing untranslated regions that include regulatory elements such as five Sp1 binding sites.^[10] The intron-exon boundaries adhere to the GT-AG consensus rule, ensuring accurate splicing during mRNA processing, and the nine introns vary in length but collectively occupy the majority of the genomic span.^[11] The promoter region, located upstream of exon 1, spans about 1.2 kb and features sterol regulatory elements (SRE-1 and SRE-2) that enable sterol-dependent transcriptional activation via SREBP-1a and SREBP-2 transcription factors. Evolutionarily, the IDH1 gene demonstrates strong conservation across eukaryotes, underscoring the essential metabolic function of its encoded enzyme in NADPH production and redox balance. Orthologs exist in diverse species, including the yeast Saccharomyces cerevisiae, where the cytosolic NADP-specific isocitrate dehydrogenase is encoded by IDP2 (YOR347C), sharing approximately 60% sequence identity with human IDH1. Bacterial homologs, such as the icd gene products in Escherichia coli, further highlight prokaryotic origins of this enzyme family, with conserved catalytic domains facilitating isocitrate oxidation in the tricarboxylic acid cycle.

Tissue Expression

Isocitrate dehydrogenase 1 (IDH1) exhibits ubiquitous mRNA expression across human tissues, reflecting its fundamental role in cellular metabolism, though levels vary considerably by tissue type. Data from the Genotype-Tissue Expression (GTEx) project indicate median transcripts per million (TPM) values ranging from approximately 100 TPM in low-expressing tissues to over 500 TPM in high-expressing ones. The highest expression is observed in the testis (median 600 TPM), liver (median 500 TPM), and adrenal gland (median 400 TPM), with kidney cortex (median 300 TPM) and heart left ventricle (median 200 TPM). In contrast, expression is lower in the brain (e.g., median 100 TPM in cerebellum), skeletal muscle, and adipose tissue (median 100 TPM in subcutaneous adipose), as well as in whole blood, skin, and esophageal mucosa (all around 100 TPM). At the protein level, IDH1 displays a consistent cytoplasmic expression pattern with granular localization in multiple tissues, as documented by immunohistochemistry in the Human Protein Atlas; it is particularly abundant in glandular cells of the prostate and other male reproductive tissues, aligning with high mRNA levels in this system.^[12]^[13]^[14] IDH1 expression is modulated by metabolic cues, including responses to oxygen availability via hypoxia-inducible factors (HIFs). In hypoxic environments, HIF-1α transcriptionally represses IDH1 in specific contexts, such as osteosarcoma cells, thereby adapting cellular metabolism to low-oxygen conditions by shifting away from oxidative pathways. Glucose levels indirectly influence IDH1 through broader metabolic signaling, though direct transcriptional regulation remains less characterized; however, IDH1 mRNA and activity respond to nutrient availability in tissues like the liver, where fasting or high-glucose states alter cytosolic NADP+-dependent dehydrogenase dynamics. These regulatory mechanisms ensure IDH1 supports NADPH production and redox balance in response to fluctuating metabolic demands.^[15]^[16] Developmentally, IDH1 expression undergoes dynamic changes, particularly during adipogenesis. In brown adipose tissue differentiation, IDH1 mRNA is upregulated, and the enzyme's production of α-ketoglutarate (α-KG) is essential for promoting thermogenic gene programs and mitochondrial biogenesis in precursor cells. This upregulation facilitates epigenetic modifications via α-KG-dependent dioxygenases, enhancing adipocyte maturation and metabolic adaptation in response to cold or developmental cues. Such patterns underscore IDH1's role in tissue-specific differentiation beyond constitutive expression.^[17]

Protein Structure

Monomer Architecture

The monomer of human isocitrate dehydrogenase 1 (IDH1), a 414-amino-acid polypeptide, exhibits a tripartite domain organization that underpins its structural integrity and cofactor binding. The large domain, spanning residues 1–103 and 286–414, adopts a canonical Rossmann fold characterized by alternating α-helices and β-strands, which forms the primary binding site for the NADP⁺ cofactor through conserved dinucleotide-binding motifs.^[18] This fold is evolutionarily conserved among NADP-dependent dehydrogenases and positions the nicotinamide ring for hydride transfer during catalysis.^[18] Adjacent to the large domain, the small domain (residues 104–136 and 186–285) consists of an α/β sandwich fold, featuring a central β-sheet flanked by α-helices, which contributes to the overall scaffold and interfaces with the active site cleft.^[18] The clasp domain (residues 137–185), a flexible linker-like region, bridges the large and small domains, stabilizing the monomer's tertiary structure and facilitating substrate access to the active site.^[18] The active site resides in a cleft between the large and small domains, where key residues coordinate substrate binding and orientation. Notably, Arg132, located in the small domain, forms hydrogen bonds with the β-carboxyl group of isocitrate, ensuring precise substrate positioning for oxidative decarboxylation.^[19] This residue is highly conserved and represents a mutational hotspot due to its central role in catalysis.^[20] High-resolution crystal structures, such as the 2.70 Å structure of wild-type IDH1 in complex with NADP⁺ (PDB entry 1T09), illustrate the open conformation of the monomer, with the clasp domain in an extended state that allows cofactor accommodation without substrate.^[21] These structures confirm the domain boundaries and reveal intramolecular hydrogen bonding networks that maintain the Rossmann fold's rigidity.

Dimer Assembly

Isocitrate dehydrogenase 1 (IDH1) assembles as a homodimer, with each monomer consisting of a large domain, a small domain, and a clasp domain that plays a central role in subunit interactions. The clasp domain, comprising residues approximately 137–185, forms the primary contact points at the dimer interface, enabling the two monomers to associate tightly and create the functional quaternary structure. This assembly is essential for enzymatic activity, as the active sites are located in clefts flanked by the clasp domain from one subunit and residues from the large and small domains of the other subunit.^[22] Dimerization stabilizes the active sites by positioning critical catalytic residues, such as those involved in substrate coordination and hydride transfer, across the subunit boundary. Without proper dimer formation, the enzyme exhibits reduced stability and impaired catalysis, as demonstrated by mutagenesis studies disrupting interface contacts. Furthermore, the dimer interface facilitates allosteric regulation, where perturbations at this site can influence cofactor binding and overall enzyme conformation, modulating activity in response to cellular conditions.^[22]^[23] Ligand binding induces structural changes that propagate through the dimer. For instance, NADP⁺ binding to the small domain triggers local conformational shifts, including adjustments in loop regions near the interface, which enhance cofactor affinity and prepare the active site for isocitrate accommodation. These changes involve rigid-body movements of the large domain toward the clasp region, closing the active site cleft and promoting productive substrate orientation within the homodimer.^[22]

Biochemical Function

Enzymatic Mechanism

Isocitrate dehydrogenase 1 (IDH1) catalyzes the NADP⁺-dependent oxidative decarboxylation of isocitrate to α-ketoglutarate in the cytosol and peroxisomes, producing NADPH as a key reducing agent for biosynthetic processes and antioxidant defense. The overall reaction is represented by the equation:

\text{isocitrate} + \text{NADP}^+ \rightarrow \alpha\text{-ketoglutarate} + \text{CO}_2 + \text{NADPH} + \text{H}^+

This reversible process favors the forward direction under typical cellular conditions, linking carbohydrate metabolism to NADPH generation.^[24] The catalytic mechanism occurs in two discrete steps. In the first step, the secondary alcohol at the C2 position of isocitrate is oxidized to a ketone, yielding the unstable β-keto acid intermediate oxalosuccinate and reducing NADP⁺ to NADPH; this step involves hydride transfer from the substrate to the cofactor. The second step involves the β-decarboxylation of oxalosuccinate, releasing CO₂ and forming the enol tautomer of α-ketoglutarate, which then tautomerizes to the keto form. IDH1 requires a divalent cation cofactor, either Mn²⁺ or Mg²⁺ (with Mg²⁺ preferred physiologically), which binds at the active site to chelate the α- and γ-carboxylate groups of isocitrate, polarizing the substrate for oxidation and stabilizing the intermediate. The metal ion also interacts with conserved residues such as Asp and Ser to position the substrate optimally.^[25]^[26] Kinetic characterization of wild-type human IDH1 reveals high substrate affinity and efficient turnover. The Michaelis constant (Km) for isocitrate is approximately 15–220 μM depending on assay temperature (lower at room temperature, higher at 37°C), with a turnover number (kcat) of 11 s⁻¹ at 21°C or 85 s⁻¹ at 37°C in the presence of Mg²⁺ and at pH 7.5. These parameters underscore IDH1's role as an effective generator of NADPH at low substrate concentrations typical of cellular environments.^[26]

Physiological Roles

Isocitrate dehydrogenase 1 (IDH1) plays a central role in cellular metabolism by generating NADPH through the oxidative decarboxylation of isocitrate to α-ketoglutarate, primarily in the cytosol and peroxisomes. This NADPH serves as a key reducing agent for anabolic processes, including the synthesis of fatty acids and cholesterol, which are essential for membrane biogenesis and energy storage in proliferating cells. In hepatocytes, IDH1 specifically supports peroxisomal lipid synthesis by providing NADPH for fatty acid elongation and desaturation, regulated by sterol regulatory element-binding proteins.^[27]^[28] Beyond biosynthesis, IDH1 contributes to cellular antioxidant defense by fueling the regeneration of reduced glutathione (GSH) from its oxidized form (GSSG) via glutathione reductase. This process neutralizes reactive oxygen species (ROS), maintaining redox homeostasis and protecting cells from oxidative damage, particularly in environments with high metabolic activity. The enzyme's localization in the cytosol enables broad support for these reductive reactions, while its peroxisomal presence aids in detoxifying ROS generated during β-oxidation of fatty acids, thus linking lipid catabolism to redox balance.^[29] Under hypoxic conditions or mitochondrial dysfunction, IDH1 exhibits reversible activity, catalyzing the reductive carboxylation of α-ketoglutarate to isocitrate using NADPH. This reverse reaction replenishes tricarboxylic acid (TCA) cycle intermediates and generates isocitrate, which can be converted to citrate for subsequent lipogenesis, sustaining cellular viability and biosynthetic demands in low-oxygen settings. Such adaptability underscores IDH1's role in metabolic flexibility during stress.^[30]^[31]

Mutations

Recurrent Variants

The most recurrent genetic variants in IDH1 are heterozygous missense point mutations clustered at codon 132 of the active site, which account for nearly all reported IDH1 alterations in tumors.00098-5) In gliomas, the arginine-to-histidine substitution (R132H) predominates, comprising over 90% of IDH1 mutations, while variants such as R132C and R132G are more frequent in acute myeloid leukemia (AML).30182-X) These mutations are almost exclusively somatic and heterozygous, preserving one wild-type allele.^[32] IDH1 codon 132 mutations exhibit high prevalence in specific malignancies, occurring in 70-80% of low-grade gliomas and secondary glioblastomas, where they represent an early oncogenic event.00098-5) In AML, the prevalence is lower at 15-20% for IDH1/2 mutations combined, with IDH1 R132 variants contributing about 7-8% of cases.^[32] IDH1 codon 132 mutations also occur in other solid tumors, such as chondrosarcomas (approximately 35-40%) and intrahepatic cholangiocarcinomas (approximately 15%), though at lower frequencies than in gliomas.^[33]^[34]00098-5) Detection of these recurrent IDH1 variants typically relies on PCR-based Sanger sequencing to identify the precise nucleotide changes at codon 132, offering high specificity for heterozygous mutations.60089-X/fulltext) Immunohistochemistry using antibodies specific to the R132H mutant protein provides a rapid, cost-effective alternative for gliomas, with sensitivity exceeding 90% for this variant, though it misses non-R132H mutations.^[35] Elevated levels of the oncometabolite 2-hydroxyglutarate (2-HG) can also serve as an indirect biomarker, detectable via mass spectrometry or magnetic resonance spectroscopy, correlating strongly with IDH1 mutation status across tumor types.^[36]

Functional Consequences

Mutations in IDH1 confer a neomorphic gain-of-function activity, enabling the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), specifically the R-enantiomer.^[37] This aberrant reaction is represented by the equation:

\alpha\text{-KG} + \text{NADPH} + \text{H}^{+} \rightarrow \text{R-2-HG} + \text{NADP}^{+}

^[37] In addition to this novel activity, IDH1 mutations result in a profound loss of the enzyme's wild-type function, which normally involves the NADP⁺-dependent oxidative decarboxylation of isocitrate to produce α-KG and NADPH.^[37] Consequently, cells harboring mutant IDH1 exhibit reduced production of NADPH and α-KG, exacerbating metabolic imbalances as the mutant enzyme consumes these substrates to generate 2-HG.^[37]^[38] The accumulation of 2-HG acts as an oncometabolite that competitively inhibits α-KG-dependent dioxygenases, including TET family enzymes responsible for DNA demethylation and JmjC-domain-containing histone demethylases.^[39] Inhibition of TET enzymes, such as TET2, impairs the hydroxylation of 5-methylcytosine, leading to DNA hypermethylation and altered gene expression patterns.^[39] Similarly, suppression of histone demethylases increases histone methylation levels, further disrupting chromatin structure.^[39] These epigenetic perturbations drive cellular reprogramming, including the blockade of differentiation and promotion of a stem-like state conducive to tumorigenesis.^[39] For instance, in hematopoietic cells, 2-HG exposure inhibits myeloid differentiation, an effect reversible upon metabolite clearance.^[39]

Clinical Significance

Role in Cancer

Mutations in IDH1 serve as oncogenic drivers in several malignancies, particularly adult-type diffuse gliomas, acute myeloid leukemia (AML), and intrahepatic cholangiocarcinoma (iCCA). In gliomas, IDH1 mutations are found in approximately 70-80% of low-grade cases and define the entity of astrocytoma, IDH-mutant, according to the 2021 World Health Organization (WHO) classification of central nervous system tumors, which encompasses grades 2-4 tumors characterized by diffuse astrocytic infiltration and absence of 1p/19q codeletion.^[40]^[32] In AML, IDH1 mutations occur in 6-16% of cases, acting as early driver events that contribute to leukemogenesis through epigenetic dysregulation.^[41] Similarly, in iCCA, IDH1 mutations are detected in 13-20% of tumors, representing a recurrent early alteration that promotes tumorigenesis via neomorphic enzyme activity.^[42]^[43] The primary mechanism underlying IDH1's oncogenic role involves the production of the oncometabolite 2-hydroxyglutarate (2-HG) by mutant enzyme, which competitively inhibits α-ketoglutarate-dependent dioxygenases, leading to widespread epigenetic changes such as DNA and histone hypermethylation. In gliomagenesis, elevated 2-HG levels stabilize hypoxia-inducible factor 1α (HIF-1α), enhancing pseudohypoxic signaling and promoting tumor cell survival under stress.^[44] Additionally, 2-HG induces metabolic rewiring by altering the tricarboxylic acid cycle and redirecting carbon flux toward biosynthetic pathways, fostering glioma cell proliferation and invasion.^[45] IDH1 mutations are integral to cancer classification and prognostication, often indicating a more favorable outcome in certain contexts. In gliomas, IDH-mutant tumors exhibit longer overall survival—median up to 10 years for grade 2 cases—compared to IDH-wildtype counterparts, partly due to enhanced sensitivity to radiotherapy and chemotherapy.^[46]^[47] A 2025 analysis of immune checkpoint inhibitor therapy in recurrent gliomas reported improved progression-free survival in IDH-mutant oligodendrogliomas relative to IDH-wildtype tumors, highlighting potential immunotherapy benefits in this subset.^[48]

Role in Non-Cancer Diseases

Isocitrate dehydrogenase 1 (IDH1) plays a significant role in non-cancerous developmental disorders through somatic mosaic mutations, particularly the recurrent R132 variant, which leads to the production of the oncometabolite 2-hydroxyglutarate (2-HG). These mutations disrupt normal cellular metabolism in chondrocytes, promoting abnormal cartilage growth and resulting in enchondromas, benign tumors within the bone marrow. In Ollier disease, multiple enchondromas develop asymmetrically along the metaphyses of long bones, often causing skeletal deformities, limb length discrepancies, and functional impairments such as pain or fractures.^[49] Maffucci syndrome extends these features by incorporating vascular malformations like hemangiomas, increasing risks of thrombosis and hemorrhage alongside the cartilaginous lesions.^[49] The R132C mutation in IDH1 is the most prevalent, identified in approximately 65% of cases across both syndromes, with overall mutation detection rates exceeding 90% in affected tumors.^[49] These post-zygotic somatic mosaic events occur early in embryonic development, leading to low-level mutant allele frequencies in non-lesional tissues and higher enrichment in enchondromas, where 2-HG accumulation inhibits histone and DNA demethylases, thereby altering gene expression and sustaining chondrocyte proliferation.^[49] Patients with these syndromes face a substantially elevated risk of malignant transformation, with up to 30-50% of enchondromas progressing to chondrosarcomas, underscoring the premalignant potential of IDH1 dysregulation despite the primarily benign nature of the disorders.^[49] Somatic IDH1 mutations are also implicated in isolated enchondromatosis, where they drive similar chondrocyte persistence and tumor formation adjacent to growth plates, as demonstrated in murine models expressing mutant IDh1, which recapitulate enchondroma development without systemic effects.^[50] In 2025, a phase I clinical trial of the IDH1 inhibitor ivosidenib in patients with IDH1-mutant conventional chondrosarcoma—often arising from enchondromatosis—reported manageable toxicity, with 71.4% of participants experiencing mostly low-grade adverse events such as diarrhea and nausea, and promising efficacy including an objective response rate of 23.1% and a median duration of response of 53.5 months among 13 evaluable patients.^[51] Beyond skeletal disorders, IDH1 mutations contribute to rare metabolic conditions characterized by 2-HG accumulation, such as D-2-hydroxyglutaric aciduria (D-2-HGA), a neurometabolic disorder involving developmental delay, seizures, and hypotonia. Mosaic IDH1 variants, particularly R132, have been detected in cases of metaphyseal chondromatosis with D-2-HGA (MC-HGA), where they confer neomorphic activity, converting α-ketoglutarate to D-2-HG and elevating urinary levels of D-2-HG, mimicking the enzyme deficiency in primary D-2-HGA caused by D2HGDH mutations.^[52] This 2-HG buildup inhibits α-ketoglutarate-dependent dioxygenases, disrupting epigenetics and potentially exacerbating neurological symptoms, though such IDH1-associated cases represent a minority compared to classical forms.

Therapeutic Targeting

Inhibitor Development

The development of inhibitors for mutant isocitrate dehydrogenase 1 (IDH1) has focused on exploiting structural differences between the wild-type and mutant enzymes, particularly the recurrent R132 variants prevalent in cancers such as gliomas and acute myeloid leukemia. Structure-based drug design has been pivotal, utilizing X-ray crystallography to identify an allosteric binding pocket at the dimer interface adjacent to the R132 residue in the active site. This pocket is accessible in the mutant form due to conformational changes induced by the R132 substitution, allowing selective inhibition of the neomorphic activity that converts α-ketoglutarate (α-KG) to the oncometabolite 2-hydroxyglutarate (2-HG). Inhibitors bind here, stabilizing an inactive "open" conformation of the mutant enzyme, thereby blocking 2-HG production while sparing the wild-type enzyme's oxidative decarboxylation of isocitrate to α-KG.^[53] Early efforts at Agios Pharmaceuticals yielded AGI-5198 as a seminal allosteric inhibitor through optimization of hits from a high-throughput screen against R132H-IDH1. With an IC50 of approximately 70 nM for R132H and 160 nM for R132C mutants, AGI-5198 demonstrates over 100-fold selectivity for mutant over wild-type IDH1, achieved via key interactions with residues like Arg119 and the Val255/Met259 pocket in the allosteric site. By competitively inhibiting with respect to α-KG and noncompetitively with NADPH, it prevents the reductive carboxylation reaction, reducing intracellular 2-HG levels by up to 90% in mutant cells and restoring α-KG production to levels approaching those in wild-type cells. This mechanism reverses the metabolic and epigenetic perturbations driven by 2-HG, such as DNA and histone hypermethylation.^[54]^[55] Preclinical studies have validated the efficacy of these inhibitors in relevant models. In IDH1 R132H-mutant TS603 human glioma cells, AGI-5198 treatment dose-dependently inhibited proliferation and induced differentiation, marked by increased expression of astroglial markers like GFAP and reduced neural stem cell marker NES, alongside decreased repressive histone marks such as H3K9me3. In orthotopic xenograft models of mutant IDH1 gliomas in mice, oral dosing at 450 mg/kg achieved 80-90% intratumoral 2-HG reduction, slowing tumor growth by 50-60% without impacting wild-type IDH1 xenografts, thus highlighting the therapeutic potential of mutant-selective targeting. Similar effects were observed in isogenic cell lines and primary acute myeloid leukemia samples, where inhibitors promoted myeloid differentiation and impaired colony formation.^[55]^[53]

Approved and Emerging Therapies

Ivosidenib (Tibsovo) was first approved by the FDA in July 2018 for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) harboring a susceptible IDH1 mutation, based on phase 1/2 trial data showing an overall response rate of 41.6% and median duration of response of 8.2 months. Subsequent approvals expanded its use: in May 2022 as frontline therapy combined with azacitidine for newly diagnosed AML in patients unsuitable for intensive chemotherapy (aged 75 years or older or with comorbidities), demonstrating improved overall survival of 24.0 months versus 7.9 months with azacitidine alone in the AGILE phase 3 trial; and in February 2022 for previously treated, locally advanced or metastatic cholangiocarcinoma with IDH1 mutation, with an objective response rate of 6%. In October 2023, it received approval for relapsed or refractory myelodysplastic syndromes (MDS) with IDH1 mutation, showing a complete remission rate of 39%. Olutasidenib (Rezlidhia) gained FDA approval in December 2022 for adult patients with relapsed or refractory AML and a susceptible IDH1 mutation, supported by phase 2 trial results indicating a complete remission rate of 35% and median duration of 8.0 months. This oral inhibitor offers an alternative for patients intolerant to ivosidenib, with similar pharmacodynamic effects on mutant IDH1. Vorasidenib (Voranigo), a brain-penetrant dual IDH1/IDH2 inhibitor, was approved by the FDA in August 2024 for adult and pediatric patients aged 12 years and older with grade 2 astrocytoma or oligodendroglioma harboring a susceptible IDH1 or IDH2 mutation following surgery, marking the first targeted therapy for this indication. The approval stemmed from the phase 3 INDIGO trial, which reported a median progression-free survival of 27.7 months versus 11.1 months with placebo, with an objective response rate of 19% in the vorasidenib arm. Extended follow-up as of November 2025 confirmed a 65% reduction in the risk of death. The European Medicines Agency granted approval in September 2025 for the same indication. Emerging therapies focus on combinations to enhance efficacy in IDH1-mutant cancers. Long-term data from the AGILE trial as of July 2025 confirmed sustained benefits of ivosidenib plus azacitidine (a DNMT inhibitor) in newly diagnosed IDH1-mutant AML, with median overall survival of 29.3 months and 24-month overall survival rates of 53% versus 17% for azacitidine plus placebo.^[56] Preclinical and early-phase studies explore IDH1 inhibitors combined with CDK4/6 inhibitors like palbociclib in IDH-mutant gliomas and chondrosarcomas to target cell cycle dysregulation, showing synergistic growth inhibition in models.^[57] As of November 2025, phase 3 trials such as CHONQUER evaluate ivosidenib monotherapy in advanced IDH1-mutant chondrosarcoma, with interim data indicating disease control rates up to 50% in phase 1 expansion cohorts, though full approval is pending.^[58] Perioperative trials in IDH-mutant low-grade gliomas report 2-hydroxyglutarate (2-HG) reductions of over 90% with neoadjuvant IDH inhibition, correlating with delayed progression in 30-50% of cases.^[59] Common adverse effects across approved IDH1 inhibitors include differentiation syndrome, occurring in 10-25% of patients and managed with corticosteroids and hydroxyurea, and QT interval prolongation, reported in up to 24% with ivosidenib and requiring ECG monitoring.^[60] Efficacy is often monitored via serial 2-HG levels in plasma or tumor tissue, with reductions exceeding 70% within days confirming on-target activity and predicting response.^[61]

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We confirmed by immunohistochemistry the expression of mutant IDH1 R132H protein in all tumor samples carrying the IDH1 G395A genetic mutation using a mutation- ...
[33]
Cancer-associated IDH1 mutations produce 2-hydroxyglutarate - PMC
Here we show that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(−)-2 ...
[34]
The common feature of leukemia-associated IDH1 and IDH2 ...
The somatic mutations in cytosolic isocitrate dehydrogenase 1 (IDH1) observed in gliomas can lead to the production of 2-hydroxyglutarate (2HG).Idh2 Is Mutated In Aml · Figure 1. Idh1 R132 And Idh2... · Figure 4. Both Idh1 And Idh2...
[35]
R-2-hydroxyglutarate as the key effector of IDH mutations promoting ...
R-2-HG, produced by mutant IDH, promotes tumor growth by inhibiting DNA/histone demethylases, leading to epigenetic changes and tumorigenesis.
[36]
The WHO 2021 Classification of Central Nervous System tumours
Jul 26, 2022 · Adult-type diffuse gliomas now constitute only 3 categories: astrocytoma IDH-mutant; oligodendroglioma, IDH-mutant and 1p/19-codeleted and ...
[37]
IDH1/IDH2 Inhibition in Acute Myeloid Leukemia - Frontiers
Mar 28, 2021 · This review highlights recent advances on metabolic deregulation in AML and novel strategies for tailored therapy targeting mutations in IDH1 and IDH2.Abstract · Introduction · Metabolic Rewiring and... · Targeting IDH1 Mutants in...
[38]
Frequent Mutation of Isocitrate Dehydrogenase (IDH)1 and IDH2 in ...
Most notably, IDH1 was the most frequently mutated gene in cholangiocarcinomas (eight of 62 samples, 13%) (Fig. 1), and mutations occurred exclusively in ...Results · Mutational Profiling Of... · Idh1 And Idh2 Mutations...
[39]
IDH Mutant Cholangiocarcinoma: Pathogenesis, Management, and ...
Mutations in isocitrate dehydrogenase (IDH) genes are among the most frequently encountered molecular alterations in cholangiocarcinoma (CCA).
[40]
The Roles of 2-Hydroxyglutarate - Frontiers
Mutations of IDH1 and IDH2 endow them the neomorphic enzyme activity to convert α-KG to D-2HG. L-2HG and D-2HG are removed by L2HGDH and D2HGDH from the ...<|control11|><|separator|>
[41]
The effects of 2-hydroxyglutarate on the tumorigenesis of gliomas
Indeed, 70% of gliomas are associated with a gain-of-function IDH mutation and consequently synthesize the oncometabolite, 2-hydroxyglutarate (2-HG). This ...Missing: functional | Show results with:functional
[42]
How gene mutations alter deadly brain cancer
May 23, 2017 · In contrast, median survival for patients with IDH-mutant gliomas can be five or even 10 years, depending on the specific tumor type.
[43]
IDH mutant high-grade gliomas - Frontiers
IDH mutant gliomas have distinct clinical, pathological, and molecular features including a favorable prognosis and response to therapy compared to their ...
[44]
The impact of IDH mutation and 1p/19q codeletion on immune ...
May 28, 2025 · Conclusions: Patients with recurrent OLIGO gliomas may have a longer PFS with ICI therapy compared with recurrent IDH-WT and IDH-MUT gliomas.
[45]
Ollier disease and Maffucci syndrome are caused by somatic mosaic ...
Nov 6, 2011 · In summary, we have demonstrated that IDH1 mutations are common events in tumors in both Ollier disease and Maffucci syndrome, providing genetic ...Missing: germline | Show results with:germline
[46]
Mutant IDH is sufficient to initiate enchondromatosis in mice - PNAS
These data show that mutant Idh in growth-plate cells causes persistence of chondrocytes, giving rise to enchondromas adjacent to the growth cartilage in bone.
[47]
Phase I Study of the Mutant IDH1 Inhibitor Ivosidenib - AACR Journals
A phase I study demonstrated that ivosidenib, a mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor, showed manageable toxicity and durable disease control ...
[48]
Novel cases of D-2-hydroxyglutaric aciduria with IDH1 or IDH2 ...
Mosaicism for IDH2 mutations has not previously been reported as a cause of D-2HGA. Here we describe three cases: one MC-HGA case with IDH1 mosaic mutations, ...
[49]
https://www.nature.com/articles/ng.994
[50]
https://www.pnas.org/doi/10.1073/pnas.1424400112
[51]
https://aacrjournals.org/clincancerres/article/31/11/2108/762527/Phase-I-Study-of-the-Mutant-IDH1-Inhibitor
[52]
Long-term results from the AGILE study of azacitidine plus ...
CLINICAL TRIALS AND OBSERVATIONS| October 15, 2025. Long-term results from the AGILE study of azacitidine plus ivosidenib vs placebo in newly diagnosed IDH1 ...
[53]
Targeting IDH-Mutant Glioma - ScienceDirect.com
CDK4/6 inhibitors, which are used in advanced, hormone-positive breast cancer, offer the potential to target this signaling axis at the recurrent phase.
[54]
NCT06127407 | Ivosidenib in Participants With Locally Advanced or ...
Phase I Study of the Mutant IDH1 Inhibitor Ivosidenib: Long-term Safety and Clinical Activity in Patients with Conventional Chondrosarcoma. Clin Cancer Res ...
[55]
Perioperative IDH inhibition in treatment-naive IDH-mutant glioma
Aug 21, 2025 · ... IDH1 activating mutations. Six (60%) participants were enrolled at ... Whole blood was centrifuged 1,500 × g for 10 min at 4 °C, and ...
[56]
Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or ...
Jun 2, 2018 · Prolongation of the QT interval was reported in 44 patients (24.6%) with relapsed or refractory AML whose starting dose of ivosidenib was 500 mg ...
[57]
Pharmacodynamics of mutant-IDH1 inhibitors in glioma patients ...
Apr 16, 2018 · Our results from a Phase 1 clinical trial indicate a rapid decrease of 2HG levels by 70% (CI 13%, P = 0.019) after 1 week of treatment.Results · Tumor 2hg Levels Decrease... · Idh1 Mutations