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Mutant IDH1 inhibitor

CAS# 1429180-08-4

Mutant IDH1 inhibitor

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Chemical structure

Mutant IDH1 inhibitor

3D structure

Chemical Properties of Mutant IDH1 inhibitor

Cas No. 1429180-08-4 SDF Download SDF
PubChem ID 71542482 Appearance Powder
Formula C25H34N6O3 M.Wt 466.58
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : ≥ 34 mg/mL (72.87 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name (4S)-3-[2-[[(1S)-1-[4-[(4-acetylpiperazin-1-yl)methyl]phenyl]ethyl]amino]pyrimidin-4-yl]-4-propan-2-yl-1,3-oxazolidin-2-one
SMILES CC(C)C1COC(=O)N1C2=NC(=NC=C2)NC(C)C3=CC=C(C=C3)CN4CCN(CC4)C(=O)C
Standard InChIKey BEWLUEOYYPKPQL-PGRDOPGGSA-N
Standard InChI InChI=1S/C25H34N6O3/c1-17(2)22-16-34-25(33)31(22)23-9-10-26-24(28-23)27-18(3)21-7-5-20(6-8-21)15-29-11-13-30(14-12-29)19(4)32/h5-10,17-18,22H,11-16H2,1-4H3,(H,26,27,28)/t18-,22+/m0/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Mutant IDH1 inhibitor

DescriptionMutant IDH1 inhibitor is a potent mutant IDH1 R132H inhibitor with IC50 of < 72 nM.In Vitro:Mutant IDH1 inhibitor is a potent IDH1 R132H inhibitor, and used for the treatment of diseases or disorders associated with such mutant IDH proteins including, but not limited to, cell-proliferation disorders, such as cancer[1].

References:
[1]. 3-Pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH and their preparation. Patent WO 2013046136 A1 20130404

Protocol

Cell Assay [1]
Day 1: cells are seeded in 384-well plates in triplicates for both the cell proliferation and 2HG assay, and incubated at 37°C, 95% Rh, 5% CO2 overnight. Day 2: compounds are serially diluted 1 :3 (10 point dilution from 10 mM solutions in DMSO) and delivered to the cell assay plates via acoustic dispenser, with final concentration ranging from 30 μM to 1.5 nM. The plates are returned to the incubator after treatment and incubated for 48 hours. Day 4 Proliferation assay: CTG is added to the assay plates and luminescence signal is read on the plate reader. Day 4 2HG assay : Extraction sample preparation consisted of aspirating all media from the assay plates, adding 70 μL of 90% methanol in water, dry ice incubation for 15 minutes, centrifuging at 2000 rpm for 30 min to ensure all particulates have settled, and transferring 30 μL of the supernatant into LC-MS ready plates. LC-MS analysis follows.

References:
[1]. 3-Pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH and their preparation. Patent WO 2013046136 A1 20130404

Mutant IDH1 inhibitor Dilution Calculator

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Mutant IDH1 inhibitor Molarity Calculator

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Preparing Stock Solutions of Mutant IDH1 inhibitor

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.1433 mL 10.7163 mL 21.4326 mL 42.8651 mL 53.5814 mL
5 mM 0.4287 mL 2.1433 mL 4.2865 mL 8.573 mL 10.7163 mL
10 mM 0.2143 mL 1.0716 mL 2.1433 mL 4.2865 mL 5.3581 mL
50 mM 0.0429 mL 0.2143 mL 0.4287 mL 0.8573 mL 1.0716 mL
100 mM 0.0214 mL 0.1072 mL 0.2143 mL 0.4287 mL 0.5358 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on Mutant IDH1 inhibitor

Mutant IDH1 Inhibitor is a potent mutant IDH1 R132H inhibitor with IC50 of < 72 nM.

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References on Mutant IDH1 inhibitor

Pan-mutant IDH1 inhibitor BAY 1436032 for effective treatment of IDH1 mutant astrocytoma in vivo.[Pubmed:28124097]

Acta Neuropathol. 2017 Apr;133(4):629-644.

Mutations in codon 132 of isocitrate dehydrogenase (IDH) 1 are frequent in diffuse glioma, acute myeloid leukemia, chondrosarcoma and intrahepatic cholangiocarcinoma. These mutations result in a neomorphic enzyme specificity which leads to a dramatic increase of intracellular D-2-hydroxyglutarate (2-HG) in tumor cells. Therefore, mutant IDH1 protein is a highly attractive target for inhibitory drugs. Here, we describe the development and properties of BAY 1436032, a pan-inhibitor of IDH1 protein with different codon 132 mutations. BAY 1436032 strongly reduces 2-HG levels in cells carrying IDH1-R132H, -R132C, -R132G, -R132S and -R132L mutations. Cells not carrying IDH mutations were unaffected. BAY 1436032 did not exhibit toxicity in vitro or in vivo. The pharmacokinetic properties of BAY 1436032 allow for oral administration. In two independent experiments, BAY 1436032 has been shown to significantly prolong survival of mice intracerebrally transplanted with human astrocytoma carrying the IDH1R132H mutation. In conclusion, we developed a pan-inhibitor targeting tumors with different IDH1R132 mutations.

Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo.[Pubmed:28232670]

Leukemia. 2017 Oct;31(10):2020-2028.

Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are frequently found in several human cancer types including acute myeloid leukemia (AML) and lead to the production of high levels of the oncometabolite (R)-2-hydroxyglutarate (R-2HG). Here we report the characterization of BAY1436032, a novel pan-Mutant IDH1 inhibitor, both in vitro and in vivo. BAY1436032 specifically inhibits R-2HG production and colony growth, and induces myeloid differentiation of AML cells carrying IDH1R132H, IDH1R132C, IDH1R132G, IDH1R132L and IDH1R132S mutations. In addition, the compound impacts on DNA methylation and attenuates histone hypermethylation. Oral administration of BAY1436032 led to leukemic blast clearance, myeloid differentiation, depletion of leukemic stem cells and prolonged survival in two independent patient-derived xenograft IDH1 mutant AML mouse models. Together, BAY1436032 is highly effective against all major types of IDH1 mutant AML.

Treatment with a Small Molecule Mutant IDH1 Inhibitor Suppresses Tumorigenic Activity and Decreases Production of the Oncometabolite 2-Hydroxyglutarate in Human Chondrosarcoma Cells.[Pubmed:26368816]

PLoS One. 2015 Sep 14;10(9):e0133813.

Chondrosarcomas are malignant bone tumors that produce cartilaginous matrix. Mutations in isocitrate dehydrogenase enzymes (IDH1/2) were recently described in several cancers including chondrosarcomas. The IDH1 inhibitor AGI-5198 abrogates the ability of mutant IDH1 to produce the oncometabolite D-2 hydroxyglutarate (D-2HG) in gliomas. We sought to determine if treatment with AGI-5198 would similarly inhibit tumorigenic activity and D-2HG production in IDH1-mutant human chondrosarcoma cells. Two human chondrosarcoma cell lines, JJ012 and HT1080 with endogenous IDH1 mutations and a human chondrocyte cell line C28 with wild type IDH1 were employed in our study. Mutation analysis of IDH was performed by PCR-based DNA sequencing, and D-2HG was detected using tandem mass spectrometry. We confirmed that JJ012 and HT1080 harbor IDH1 R132G and R132C mutation, respectively, while C28 has no mutation. D-2HG was detectable in cell pellets and media of JJ012 and HT1080 cells, as well as plasma and urine from an IDH-mutant chondrosarcoma patient, which decreased after tumor resection. AGI-5198 treatment decreased D-2HG levels in JJ012 and HT1080 cells in a dose-dependent manner, and dramatically inhibited colony formation and migration, interrupted cell cycling, and induced apoptosis. In conclusion, our study demonstrates anti-tumor activity of a Mutant IDH1 inhibitor in human chondrosarcoma cell lines, and suggests that D-2HG is a potential biomarker for IDH mutations in chondrosarcoma cells. Thus, clinical trials of mutant IDH inhibitors are warranted for patients with IDH-mutant chondrosarcomas.

Evidence for Clinical Differentiation and Differentiation Syndrome in Patients With Acute Myeloid Leukemia and IDH1 Mutations Treated With the Targeted Mutant IDH1 Inhibitor, AG-120.[Pubmed:27245312]

Clin Lymphoma Myeloma Leuk. 2016 Aug;16(8):460-5.

BACKGROUND: Cancer-associated isocitrate dehydrogenase (IDH) mutations block normal cellular differentiation via production of the oncometabolite, R-2-hydroxyglutarate. In patients with acute myeloid leukemia (AML) receiving targeted mutant IDH inhibitor therapy, neutrophil recovery within the setting of clinical differentiation syndrome (DS) has been anecdotally described. PATIENTS AND METHODS: We describe 3 patients who developed clinically apparent DS during monotherapy with the Mutant IDH1 inhibitor, AG-120, for relapsed/refractory AML. RESULTS: AG-120-induced differentiation commenced within the first 60 days of treatment, notably in the same time frame as clinical response, strengthening the purported mechanism of targeted mutant IDH inhibitor therapy via successful myeloid maturation. Symptoms of DS were nonspecific and included culture-negative fever, edema, hypotension, malaise, and pleural and/or pericardial effusions, in addition to marked neutrophil-predominant leukocytosis. CONCLUSION: DS can occur during treatment with targeted Mutant IDH1 inhibitor therapy. Patients might present with nonspecific clinical manifestations often in the setting of leukocytosis related to exuberant neutrophil recovery. Prompt identification and initiation of treatment interventions, including hydroxyurea, corticosteroids, and/or consideration of temporary treatment discontinuation, are important to facilitate prompt resolution.

Description

Mutant IDH1 inhibitor is a potent mutant IDH1 R132H inhibitor with IC50 of < 72 nM.

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