Mutant Isocitrate Dehydrogenase 1 (mIDH1, e.g., R132H mutation) (IC50 = 10 nM for recombinant human mIDH1 R132H) [2]
- Mutant Isocitrate Dehydrogenase 2 (mIDH2, e.g., R140Q, R172K mutations) (IC50 = 14 nM for mIDH2 R140Q; IC50 = 12 nM for mIDH2 R172K) [2]
- No significant inhibition of wild-type IDH1/2 (wtIDH1/2) with IC50 > 10 μM, showing >1000-fold selectivity for mutant over wild-type enzymes [2]

With an IC50 of less than 50 nM, vorasidenib exhibits potent anti-proliferative activity against human glioblastoma U-87 MG pLVX-IDH2 R140Q-neo, fibrosarcoma HT-1080, and neurosphere TS603 cells [2].

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Vorasidenib (0.1-100 nM) dose-dependently inhibited 2-hydroxyglutarate (2-HG) production in mIDH1 R132H-expressing HT1080 fibrosarcoma cells, with an IC50 of 12 nM for 2-HG reduction [2]
- In mIDH2 R140Q-expressing SK-MEL-28 melanoma cells, Vorasidenib (0.5-50 nM) reduced 2-HG levels by 85% at 20 nM, restoring normal cellular metabolism [2]
- Vorasidenib exhibited antiproliferative activity in mIDH1/2-positive cancer cell lines: GI50 = 25 nM (mIDH1 R132H HT1080), GI50 = 30 nM (mIDH2 R140Q SK-MEL-28) after 72 hours; no significant effect on wtIDH1/2-expressing cells (GI50 > 5 μM) [2]
- Vorasidenib (20 nM) induced differentiation of mIDH1 R132H-positive primary acute myeloid leukemia (AML) blasts, as evidenced by increased expression of myeloid differentiation markers (CD11b, CD14) [2]

AG-881 fully penetrates the blood-brain barrier. AG-881 has been developed and is in early phase I testing for patients with IDH mutation-positive hematologic malignancies and solid tumors, including glioma.

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Nude mice bearing mIDH1 R132H HT1080 xenografts were administered Vorasidenib (50 mg/kg, oral gavage, once daily for 21 days). Tumor 2-HG levels were reduced by 90%, and tumor growth inhibition rate reached 65% [2]
- In a patient-derived mIDH2 R140Q AML xenograft (PDX) model, Vorasidenib (40 mg/kg, po, qd×28) decreased bone marrow 2-HG concentration by 88% and reduced blast infiltration by 60% [2]

In pharmacological studies, Vorasidenib exhibited excellent brain penetration and dose-dependently reduced D-2-HG levels. In pharmacokinetics studies, Vorasidenib showed rapid oral absorption and relatively low total body plasma clearance in mice (0.406 L h–1 kg–1) and rats (0.289 L h–1 kg–1). Recently, Vorasidenib entered a phase I clinical trial in patients with advanced solid tumors to investigate its PK/PD, safety, and clinical activity (NCT02481154). Another phase I clinical trial is focusing on patients with mIDH1/2 advanced hematologic cancers (NCT02492737). Excitingly, a phase I study of Vorasidenib and 4 in glioma will soon begin to evaluate the suppression of 2-HG in IDH1 mutant gliomas in resected tumor tissue after presurgical treatment with Vorasidenib or 4 (NCT03343197). [2]

Absorption
After single or multiple daily dosing, the maximum plasma concentration (Cmax) and AUC of vorasidinib increase approximately proportionally over a dose range of 10 to 200 mg (equivalent to 0.2 to 4 times the highest approved recommended dose). At the highest approved recommended dose, the steady-state mean (CV%) Cmax is 133 ng/mL (73%), and the AUC is 1,988 h × ng/mL (95%). Steady-state is reached within 28 days after once-daily dosing, with a mean cumulative ratio of AUC of 4.4. The median time to peak plasma concentration (Tmax) at steady-state is 2 hours (0.5 to 4 hours). The mean absolute bioavailability of vorasidinib is 34%. Compared to a fasting state, a high-fat, high-calorie meal (800-1000 calories, of which 500-600 calories are from fat) increased the Cmax of vorasidini by 3.1 times and the AUC by 1.4 times. A low-fat, low-calorie meal (400-500 calories, of which 100-125 calories are from fat) increased the Cmax of vorasidini by 2.3 times and the AUC by 1.4 times.
Excretion Route
After a single oral dose of radiolabeled vorasidini, 85% of the dose is excreted in feces (56% unchanged) and 4.5% in urine.
Volume of Distribution
The mean volume of distribution (coefficient of variation) of vorasidini at steady state is 3930 liters (40%). Voracildini can cross the blood-brain barrier: the ratio of brain tumor concentration to plasma concentration is 1.6.
Clearance
The mean (CV%) steady-state oral clearance is 14 L/h (56%).
Protein Binding
In vitro studies show that vorasidinib is 97% bound to proteins in human plasma, regardless of concentration.
Metabolism/Metabolites
Voracildinib is primarily metabolized via CYP1A2, with smaller contributions from CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A. Non-CYP pathways may contribute up to 30% of metabolism. The exact metabolic pathways and metabolites have not been fully elucidated.
Biological Half-Life
The mean (CV%) steady-state terminal half-life is 10 days (57%).

The most common adverse reactions (≥15%) include fatigue, headache, COVID-19 infection, musculoskeletal pain, diarrhea, nausea, and seizures. The most common grade 3 or 4 laboratory abnormalities (>2%) include elevated alanine aminotransferase, elevated aspartate aminotransferase, elevated gamma-glutamyl transferase, and neutropenia.

[1]. Targeting isocitrate dehydrogenase (IDH) in cancer. Discov Med. 2016 May;21(117):373-80.

[2]. Inhibitors of Mutant Isocitrate Dehydrogenases 1 and 2 (mIDH1/2): An Update and Perspective. J Med Chem. 2018 Oct 25;61(20):8981-9003.

Woracidinib is an oral isocitrate dehydrogenase inhibitor that inhibits mutants of cytoplasmic isocitrate dehydrogenase type 1 (IDH1, soluble [NADP+]) and mitochondrial isocitrate dehydrogenase type 2 (IDH2, mitochondrial isocitrate dehydrogenase [NADP+]), exhibiting potential antitumor activity. After administration, voracidinib specifically inhibits the IDH1 and IDH2 mutants, thereby inhibiting the production of the oncogenic metabolite 2-hydroxyglutarate (2HG) from α-ketoglutarate (α-KG). This blocks 2HG-mediated signaling and leads to differentiation induction and proliferation inhibition in tumor cells expressing IDH mutations. Furthermore, voracidinib can cross the blood-brain barrier (BBB). IDH1 and IDH2 are metabolic enzymes that catalyze the conversion of isocitrate to α-ketoglutarate (α-KG), playing crucial roles in energy production and being mutated in various cancer cell types. In addition, mutants of IDH1 and IDH2 can catalyze the production of 2-hydroxyglutaric acid (2-HG) and promote cancer growth by inhibiting cell differentiation and inducing cell proliferation.

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Vorasidenib (AG-881) is an oral, potent, selective dual inhibitor of IDH1 and IDH2 mutant enzymes[1][2]- Its mechanism of action involves binding to the allosteric sites of mIDH1/2, thereby blocking the aberrant conversion of isocitrate to 2-HG. 2-HG accumulation reduces reversible epigenetic dysregulation (e.g., histone and DNA hypermethylation) and restores normal cell differentiation [1][2] - This drug is being developed for the treatment of cancers carrying mIDH1/2 mutations, including acute myeloid leukemia (AML), low-grade glioma (LGG), and cholangiocarcinoma [1][2] - It has superior selectivity for mutant IDH enzymes compared to wild-type counterparts, thereby minimizing off-target effects on normal cell metabolism [2] - Preclinical data support its potential as a targeted therapy for mIDH1/2-driven malignancies, and ongoing clinical trials are evaluating its efficacy and safety in patients [1][2] - Vorasidenib is a first-in-class dual isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2) inhibitor. Voracinib works by inhibiting the levels of D-2-hydroxyglutarate (2-HG), a cancer metabolite produced by mutant IDH1 and IDH2 isoenzymes. Compared to other IDH inhibitors such as [ivosidenib] and [enasidenib], voracinib has better brain penetration and higher drug exposure. Voracinib was first approved by the FDA on August 6, 2024, for the treatment of grade 2 astrocytomas or oligodendrogliomas harboring susceptible IDH1 or IDH2 mutations. Voracinib is an isocitrate dehydrogenase 1 inhibitor and an isocitrate dehydrogenase 2 inhibitor. Its mechanism of action is as an isocitrate dehydrogenase 1 inhibitor, an isocitrate dehydrogenase 2 inhibitor, and a cytochrome P450 3A inducer. Vorasidenib is a small molecule drug that has completed the most Phase IV clinical trials (covering all indications) and was first approved in 2024 for the treatment of astrocytomas, with four other indications under investigation. Vorasidenib is indicated for the treatment of adult and pediatric patients aged 12 years and older with grade 2 astrocytomas or oligodendrogliomas harboring susceptible isocitrate dehydrogenase-1 (IDH1) or isocitrate dehydrogenase-2 (IDH2) mutations who require surgical treatment, including biopsy, subtotal resection, or total resection. Vorasidenib inhibits tumor growth and invasion in IDH-mutant gliomas. In patients with low-grade IDH-mutant gliomas, vorasisidenib significantly improved progression-free survival and delayed the time to next anticancer therapy. Vorasidenib reduces the concentration of 2-HG in tumors of patients with IDH1 or IDH2 mutations. Compared to untreated patients, patients treated with vorasidinib had a median posterior reduction (95% confidence interval) in the percentage of tumors containing 2-HG of 64% (22%, 88%) to 93% (76%, 98%), representing a 0.3 to 0.8-fold reduction in exposure observed at the highest recommended dose. The exposure-response relationship and time course of pharmacodynamic response of vorasidinib are not fully elucidated, therefore its safety and efficacy should not be prematurely assessed. Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) enzymes are seen in a variety of malignancies, including acute myeloid leukemia (AML) and gliomas. Mutant enzymes produce an oncogenic metabolite, D-2-hydroxyglutarate (2-HG), which promotes tumorigenesis and growth by blocking the activity of α-ketoglutarate-dependent enzymes and leading to epigenetic dysregulation (e.g., global DNA hypermethylation) and immune interference. Voracidenib is a small molecule inhibitor that targets isocitrate dehydrogenases-1 and 2 (IDH1 and IDH2). In vitro studies have shown that vorasidenib can inhibit wild-type and mutant IDH1 (including R132H) and wild-type and mutant IDH2. In cell models expressing mutant IDH1 or IDH2 proteins and in vivo tumor models, vorasidenib reduces 2-HG production and partially restores cell differentiation. Isocitrate dehydrogenase (IDH) is an enzyme essential for cellular respiration in the tricarboxylic acid cycle (TCA cycle). Recurrent mutations in IDH1 or IDH2 are prevalent in various cancers, including glioma, acute myeloid leukemia (AML), cholangiocarcinoma, and chondrosarcoma. Mutated IDH1 and IDH2 proteins have acquired functions, catalyzing the reduction of α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG) by NADPH. Cancer-associated IDH mutations block normal cell differentiation and promote tumorigenesis through the aberrant production of the oncogenic metabolite 2-HG. High levels of 2-hydroxyglutarate (2-HG) have been shown to inhibit α-ketoglutarate (α-KG)-dependent dioxygenases, including histone and DNA demethylases, which play crucial roles in regulating cellular epigenetic states. Currently, targeted inhibitors of IDH1 (AG120, IDH305), IDH2 (AG221), and pan-IDH1/2 (AG881) selectively inhibit mutant IDH proteins and induce cell differentiation in in vitro and in vivo models. Preliminary results from a phase I clinical trial of IDH inhibitors in patients with advanced hematologic malignancies showed objective response rates between 31% and 40%, with durable efficacy observed (>1 year). Furthermore, IDH inhibitors have shown early activity signals in solid tumors carrying IDH mutations, including cholangiocarcinoma and low-grade gliomas. [1] Isocitrate dehydrogenases 1 and 2 (IDH1/2) are homodimerases that catalyze the conversion of isocitrate to α-ketoglutarate (α-KG) in the tricarboxylic acid cycle. However, mutant IDH1/2 (mIDH1/2) reduces α-KG to the oncogenic metabolite 2-hydroxyglutarate (2-HG). High levels of 2-HG competitively inhibit α-KG-dependent dioxygenases involved in histone and DNA demethylation, thereby impairing normal cell differentiation and promoting tumor development. Therefore, small molecules that inhibit these mutant enzymes may have therapeutic value. In recent years, more and more mIDH1/2 inhibitors have been reported. This article reviews the molecular basis of mIDH1/2, the activity, binding modes, and clinical applications of mIDH1/2 inhibitors. We point out important future research directions for mIDH1/2 inhibitors and explore potential therapeutic strategies for developing mIDH1/2 inhibitors to treat IDH1/2 mutant tumors. [2]

C14H13CLF6N6

414.7366

414.079

C, 40.54; H, 3.16; Cl, 8.55; F, 27.48; N, 20.26

1644545-52-7

2316810-02-1 (citrate)

117817422

White to off-white solid powder

5.3

2

12

5

27

448

2

ClC1=CC=CC(C2=NC(=NC(=N2)N[C@H](C)C(F)(F)F)N[C@H](C)C(F)(F)F)=N1

QCZAWDGAVJMPTA-RNFRBKRXSA-N

InChI=1S/C14H13ClF6N6/c1-6(13(16,17)18)22-11-25-10(8-4-3-5-9(15)24-8)26-12(27-11)23-7(2)14(19,20)21/h3-7H,1-2H3,(H2,22,23,25,26,27)/t6-,7-/m1/s1

6-(6-chloropyridin-2-yl)-2-N,4-N-bis[(2R)-1,1,1-trifluoropropan-2-yl]-1,3,5-triazine-2,4-diamine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: 2.5 mg/mL (6.03 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.4 mg/mL (5.79 mM) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: 2.08 mg/mL (5.02 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 4: 2.08 mg/mL (5.02 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 5: 2.08 mg/mL (5.02 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)