AGI-5198

IDH1 inhibitor against R132 mutant,selective and cell-permeable CAS# 1355326-35-0

AGI-5198

Catalog No. BCC2293----Order now to get a substantial discount!

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Chemical structure

AGI-5198

3D structure

Chemical Properties of AGI-5198

Cas No. 1355326-35-0 SDF Download SDF
PubChem ID 56645356 Appearance Powder
Formula C27H31FN4O2 M.Wt 462.56
Type of Compound N/A Storage Desiccate at -20°C
Synonyms IDH-C35
Solubility DMSO : 7.14 mg/mL (15.44 mM; Need ultrasonic)
Chemical Name N-cyclohexyl-2-(3-fluoro-N-[2-(2-methylimidazol-1-yl)acetyl]anilino)-2-(2-methylphenyl)acetamide
SMILES CC1=CC=CC=C1C(C(=O)NC2CCCCC2)N(C3=CC(=CC=C3)F)C(=O)CN4C=CN=C4C
Standard InChIKey FNYGWXSATBUBER-UHFFFAOYSA-N
Standard InChI InChI=1S/C27H31FN4O2/c1-19-9-6-7-14-24(19)26(27(34)30-22-11-4-3-5-12-22)32(23-13-8-10-21(28)17-23)25(33)18-31-16-15-29-20(31)2/h6-10,13-17,22,26H,3-5,11-12,18H2,1-2H3,(H,30,34)
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 AGI-5198

DescriptionAGI-5198 is the first highly potent and selective inhibitor of IDH1 R132H/R132C mutants with IC50 of 0.07 μM/0.16 μM.
TargetsR132H-IDH1R132C-IDH1    
IC500.07 μM0.16 μM    

Protocol

Kinase Assay [1]
Inhibitory potency against the IDH2 R140Q and IDH2 R172K enzymes is determined in an endpoint assay in which the amount of NADPH remaining at the end of the reaction is measured by the addition of a large excess of diaphorase and resazurin. IDH2 R140Q is diluted to 0.25 μg/mL in 40 μL 1X Assay Buffer (150 mM NaCl, 50 mM potassium phosphate pH 7.5, 10 mM MgCl2, 10% glycerol, 2 mM B-ME, 0.03% BSA) and incubated for 16 hours at 25°C in the presence of 1 μL of compound in DMSO. The reaction is started with the addition of 10 μL of Substrate Mix (20 μM NADPH, 8 μM alpha-ketoglutarate, in 1X Assay Buffer) and incubated for 1 hour at 25°C. Then, remaining NADPH is measured by the addition of 25 μL of Detection Mix (36 μg/mL diaphorase, 18 μM resazurin in 1X Assay buffer), incubated for 5 minutes at 25°C, and read as described above. IDH2 R172K is assayed as for IDH2 R140Q with the following modifications: 1.25 μg/mL of protein is used, the Substrate Mix contained 50 μM NADPH and 6.4 μM alpha-ketoglutarate, and the compound is incubated for 1 hour before starting the reaction.

Cell Assay [1]
TS603 cells are grown in medium containing either AGI-5198 (1.5μM) or DMSO vehicle control. One week prior to harvest cells are ransferred to differentiation medium (DMEM F12; 15 mM HEPES; 0.06% glucose; B27 without vitamin A; N2; Insulin/transferrin; 1% FBS) containing freshly added retinoic acid (1μM). ChIP of non-crosslinked cells is then carried out using established ChIP methods. 350 μg of lysate is immunoprecipitated-using anti-H3K9Me3, H3K27me3 or Rabbit Control IgG. After washing, ChIP DNA is eluted from protein G beads and analyzed by RT-PCR using SYBR green. Relative occupancy is calculated using the standard curve method and fold enrichment versus IgG. Enrichment in AGI- 5198-treated cells is normalized to vehicle control. Means and standard deviation are calculated from 4 technical replicates.

Animal Administration [1]
SCID mice are injected subcutaneously with 106 glioma cells, which are suspended in 100 μL of a 50:50 mixture of growth media and Matrigel. Once tumors have reached a measurable size, mice are randomized into the indicated treatment groups.

References:
[1]. Rohle D, et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science. 2013 May 3;340(6132):626-30. [2]. Molenaar RJ, et al. Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198. Cancer Res. 2015 Nov 15;75(22):4790-802.

AGI-5198 Dilution Calculator

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AGI-5198 Molarity Calculator

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Preparing Stock Solutions of AGI-5198

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.1619 mL 10.8094 mL 21.6188 mL 43.2376 mL 54.047 mL
5 mM 0.4324 mL 2.1619 mL 4.3238 mL 8.6475 mL 10.8094 mL
10 mM 0.2162 mL 1.0809 mL 2.1619 mL 4.3238 mL 5.4047 mL
50 mM 0.0432 mL 0.2162 mL 0.4324 mL 0.8648 mL 1.0809 mL
100 mM 0.0216 mL 0.1081 mL 0.2162 mL 0.4324 mL 0.5405 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 AGI-5198

AGI-5198 is a selective R132H-IDH1 inhibitor which is identified through a high-throughput screen blocked, in a dose-dependent manner, the ability of the mutant enzyme (mIDH1) to produce R-2-hydroxyglutarate (R-2HG). It is also induced the expression of zinc finger and BTB domain–containing protein 16 (ZBTB16), known as promyelocytic leukemia zinc finger (PLZF), a transcriptional repressor protein which is located on chromosome 11q23 and has been shown to promote glial differentiation in the central nervous system. AGI-5198 is also able to induce the expression of genes and cell markers associated with glial-specific differentiation in glioma cell, the expression of differentiation-associated genes, reduce H3K9 trimethylaytion, and cause tumor growth inhibition.

Reference

Dan Rohle, Janeta Popovici-Muller, Nicolaos Palaskas, Sevin Turcan, Christian Grommes, Carl Campos, Jennifer Tsoi, Owen Clark, Barbara Oldrini, Evangelia Komisopoulou, Kaiko Kunii, Alicia Pedraza, Stefanie Schalm, Lee Silverman, Alexandra Miller, Fang Wang, Hua Yang, Yue Chen, Andrew Kernytsky, Marc K. Rosenblum, Wei Liu, Scott A. Biller, Shinsan M. Su, Cameron W. Brennan, Timothy A. Chan, Thomas G. Graeber, Katharine E. Yen, Ingo K. Mellinghoff. An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells. Science 340, 626 (2013)

Francine E Garrett-Bakelman, Ari M Melnick. Differentiation therapy for IDH1/2 mutant malignancies. Cell Research (2013) 23:975–977.

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References on AGI-5198

Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198.[Pubmed:26363012]

Cancer Res. 2015 Nov 15;75(22):4790-802.

Isocitrate dehydrogenase 1 (IDH1) is mutated in various types of human cancer to IDH1(R132H), a structural alteration that leads to catalysis of alpha-ketoglutarate to the oncometabolite D-2-hydroxyglutarate. In this study, we present evidence that small-molecule inhibitors of IDH1(R132H) that are being developed for cancer therapy may pose risks with coadministration of radiotherapy. Cancer cells heterozygous for the IDH1(R132H) mutation exhibited less IDH-mediated production of NADPH, such that after exposure to ionizing radiation (IR), there were higher levels of reactive oxygen species, DNA double-strand breaks, and cell death compared with IDH1 wild-type cells. These effects were reversed by the IDH1(R132H) inhibitor AGI-5198. Exposure of IDH1 wild-type cells to D-2-hydroxyglutarate was sufficient to reduce IDH-mediated NADPH production and increase IR sensitivity. Mechanistic investigations revealed that the radiosensitivity of heterozygous cells was independent of the well-described DNA hypermethylation phenotype in IDH1-mutated cancers. Thus, our results argue that altered oxidative stress responses are a plausible mechanism to understand the radiosensitivity of IDH1-mutated cancer cells. Further, they offer an explanation for the relatively longer survival of patients with IDH1-mutated tumors, and they imply that administration of IDH1(R132H) inhibitors in these patients may limit irradiation efficacy in this setting.

Description

AGI-5198 is a potent and selective mutant IDH1R132H inhibitor with an IC50 of 0.07 μM.

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