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AGI-5198 (IDH-C35), Mutant IDH1 Inhibitor

AGI-5198 (IDH-C35), Mutant IDH1 Inhibitor

$109.00
The first highly potent and selective mutant IDH1 inhibitor that was shown to have anti-tumor efficacy in vivo.
Catalog No. Unit Price Qty
M60068-2s 2 mg solid $109.00
M60068-2 10 mM in DMSO (0.433 ml) $109.00
M60068-50s 50 mg solid $750.00

Details

Product Information
Chemical Name: N-cyclohexyl-2-(N-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)acetamido)-2-(o-tolyl)acetamide
Molecular Weight: 462.56
Formula: C27H31FN4O2
Purity: ≥98%
CAS#: 1355326-35-0
Solubility: DMSO up to 100 mM
Storage: Powder: 4oC 1 year DMSO: 4oC 3 month -20oC 1 year



Biological Activity:

AGI-5198 (IDH-C35) is the first highly potent and selective mutant IDH1 inhibitor that was shown to have anti-tumor efficacy and lower tumor 2‑HG (2-hydroxyglutarate) in vivo. It inhibits IDH1 R132H mutant and R132C mutant in vitro with IC50 ~0.07 µM and ~0.16 µM, respectively, but not wild-type IDH1 or any of the examined IDH2 isoforms (IC50 > 100 μM).  AGI-5198 has good cellular activities in TS603 glioma cell line, also inhibits 2-HG production in HT1080 and U87MG cells with IC50 ~0.48 µM and IC50 ~0.07 µM, respectively. In R132H-IDH1 glioma xenografts (TS603), AGI-5198 (450 mg/kg) caused 50-60% growth inhibition with no signs of toxicity during three weeks of daily treatment, but it did not affect the growth of IDH1 wild-type glioma xenografts (TS516). Under conditions of near complete R-2HG (R-2-hydroxyglutarate) inhibition, AGI-5198 induced demethylation of histone H3K9me3 and expression of genes associated with gliogenic differentiation. Blockade of mutant IDH1 impaired the growth of IDH1-mutant—but not IDH1-wild-type—glioma cells without appreciable changes in genome-wide DNA methylation. AGI-5198 could serve as a very useful chemical probe to assess the biological consequences of IDH1 mutations and the potential of IDH1 inhibitor for treating IDH1 mutant tumors.


How to Use:

In vitro:  AGI-5198 was suggested to be used at 1.5-10µM final concentration in vitro.

In vivo: AGI-5198 could be orally dosed to mice at 150-450 mg/kg once per day for up to 3 weeks in glioma xenografts.  It could be intraperitoneally (IP) dosed to mice at 50-150 mg/kg once or twice per day (formulation: 0.5% MC and 0.2% Tween 80) in the other animal studies.


Reference:

  1. 1. Dan Rohle, et al. An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells. (2013) Science.340(6132):626-30. 
  2. 2. Janeta Popovici-Muller, et al. Discovery of the First Potent Inhibitors of Mutant IDH1 That Lower Tumor 2-HG in Vivo. (2012) ACS Med. Chem. Lett. 3 (10), pp 850–855
  3. 3. Lenny Dang, et al.  Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. (2009) Nature 462, 739-744.
  4. 4. Turcan S, et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. (2012) Nature. 483(7390):479-83.
  5. 5. Popovicimuller Janeta, et al. THERAPEUTICALLY ACTIVE COMPOSITIONS AND THEIR METHOD OF USE. (2012) PCT WO 2012009678. 


   AGI-5198_spec.pdf



Products are for research use only. Not for human use.

Description

Details

Product Information
Chemical Name: N-cyclohexyl-2-(N-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)acetamido)-2-(o-tolyl)acetamide
Molecular Weight: 462.56
Formula: C27H31FN4O2
Purity: ≥98%
CAS#: 1355326-35-0
Solubility: DMSO up to 100 mM
Storage: Powder: 4oC 1 year DMSO: 4oC 3 month -20oC 1 year



Biological Activity:

AGI-5198 (IDH-C35) is the first highly potent and selective mutant IDH1 inhibitor that was shown to have anti-tumor efficacy and lower tumor 2‑HG (2-hydroxyglutarate) in vivo. It inhibits IDH1 R132H mutant and R132C mutant in vitro with IC50 ~0.07 µM and ~0.16 µM, respectively, but not wild-type IDH1 or any of the examined IDH2 isoforms (IC50 > 100 μM).  AGI-5198 has good cellular activities in TS603 glioma cell line, also inhibits 2-HG production in HT1080 and U87MG cells with IC50 ~0.48 µM and IC50 ~0.07 µM, respectively. In R132H-IDH1 glioma xenografts (TS603), AGI-5198 (450 mg/kg) caused 50-60% growth inhibition with no signs of toxicity during three weeks of daily treatment, but it did not affect the growth of IDH1 wild-type glioma xenografts (TS516). Under conditions of near complete R-2HG (R-2-hydroxyglutarate) inhibition, AGI-5198 induced demethylation of histone H3K9me3 and expression of genes associated with gliogenic differentiation. Blockade of mutant IDH1 impaired the growth of IDH1-mutant—but not IDH1-wild-type—glioma cells without appreciable changes in genome-wide DNA methylation. AGI-5198 could serve as a very useful chemical probe to assess the biological consequences of IDH1 mutations and the potential of IDH1 inhibitor for treating IDH1 mutant tumors.


How to Use:

In vitro:  AGI-5198 was suggested to be used at 1.5-10µM final concentration in vitro.

In vivo: AGI-5198 could be orally dosed to mice at 150-450 mg/kg once per day for up to 3 weeks in glioma xenografts.  It could be intraperitoneally (IP) dosed to mice at 50-150 mg/kg once or twice per day (formulation: 0.5% MC and 0.2% Tween 80) in the other animal studies.


Reference:

  1. 1. Dan Rohle, et al. An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells. (2013) Science.340(6132):626-30. 
  2. 2. Janeta Popovici-Muller, et al. Discovery of the First Potent Inhibitors of Mutant IDH1 That Lower Tumor 2-HG in Vivo. (2012) ACS Med. Chem. Lett. 3 (10), pp 850–855
  3. 3. Lenny Dang, et al.  Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. (2009) Nature 462, 739-744.
  4. 4. Turcan S, et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. (2012) Nature. 483(7390):479-83.
  5. 5. Popovicimuller Janeta, et al. THERAPEUTICALLY ACTIVE COMPOSITIONS AND THEIR METHOD OF USE. (2012) PCT WO 2012009678. 


   AGI-5198_spec.pdf



Products are for research use only. Not for human use.

Reviews

  1. review Review by info@xcessbio.com
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    Email questions about compound AGI-5198


    Question: I have a question about AGI-5198, which I purchased from XcessBio about a month ago. Under in vivo dosing, the vehicle is listed as 0.5% MC and 0.2% Tween-80 and I'm not sure what MC is. Also, are these in water or a different vehicle? 
    Our reply: MC is Methyl Cellulose, people wrote it as CMC too. The formulation is water based. Since you are doing in vivo studies, in vivo study guidance can be downloaded at our website: http://xcessbiosciences.com/resources/10.html 

    Question: How should I store the drug once I have made it up in0.5% MC and 0.2% Tween 80? Can it be stored in the freezer and for how long? 
    Our reply: The drug dosing solution could be stored in fridge up to 7-10 days. However most of time we refresh the dosing solution every 3-5 days in order to achieve the best condition. 


    Question: I've tried to get the compound into solution and I am having some trouble. I've tried increasing both the concentrations of the MC and the Tween with no luck. Do you have any other suggestions? 
    Our reply: Could you let me know what the formula looks like? It is milk like or you can still see solid particle? Have you tried sonication? If you are doing oral dosing, usually we can do a suspension dosing when the formula looks like a homogeneous milky mixture. We need more information to give you suggestions. From the publication we really do not know their formula is a suspension or a clear solution. 
    Customer reply: The solution is white and cloudy with particles on the bottom of the tube. I would like to dose IP, as mentioned on the website and in the paper but I can't get a homogenous solution even with 2% MC and 10% Tween. On the website and in the publication, the dosing is up to 150 mg/kg but I am unable to get the drug concentrated enough to dose at 50 or 75 mg/kg giving 10 ml/kg of solution. 
    Final solution from our customer: Inject higher volumes than 10 ml/kg. If we dilute the solution for injection at 30 ml/kg, the drug goes in fine.

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