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

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.

Product information

CAS Number: 1355326-35-0

Molecular Weight: 462.56

Formula: C27H31FN4O2

Synonym:

AGI 5198

AGI5198

IDH C3

IDHC35

Chemical Name: N-cyclohexyl-2-(N-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)acetamido)-2-(o-tolyl)acetamide

Smiles: CC1=CC=CC=C1C(C(=O)NC1CCCCC1)N(C1C=C(F)C=CC=1)C(=O)CN1C=CN=C1C

InChiKey: FNYGWXSATBUBER-UHFFFAOYSA-N

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)

Technical Data

Appearance: Solid Power.

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: DMSO up to 100 mM

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥360 days if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined.

HS Tariff Code: 382200

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.

References:

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. 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. Lenny Dang, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. (2009) Nature 462, 739-744.
4. Turcan S, et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. (2012) Nature. 483(7390):479-83.
5. Popovicimuller Janeta, et al. THERAPEUTICALLY ACTIVE COMPOSITIONS AND THEIR METHOD OF USE. (2012) PCT WO 2012009678.

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