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N-[2-(Cyclohexylamino)-1-(2-methylphenyl)-2-oxoethyl]-N-(3-fluorophenyl)-2-methyl-1H-imidazole-1-acetamide; IDH-C35

Chemical

C27H31FN4O2

462.6

1355326-35-0

≥98% (NMR)

White solid.

Soluble in DMSO (10mg/ml) or ethanol (5mg/ml).

Determined by 1H-NMR.

FNYGWXSATBUBER-UHFFFAOYSA-N

AMBIENT

+4°C

-20°C

Keep cool and dry.

Stable for at least 2 years after receipt when stored at -20°C.

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• Potent and selective inhibitor of IDH1 (isocitrate dehydrogenase 1) R132H and R132C mutants in vitro with IC₅₀ values of 0.07 and 0.16µM, respectively. Does not inhibit wild-type IDH1 or any of the examined IDH2 isoforms (IC₅₀>100µM). Isocitrate dehydrogenases (IDHs) are nicotinamide adenine dinucleotide (NAD+) and NAD phosphate (NADP+)-dependent enzymes in the tricarboxylic acid cycle that catalyze oxidative decarboxylation of isocitrate producing α-ketoglutarate (2-OG) and carbon dioxide. IDH1 and IDH2 are mutated in >70% of lower grade gliomas.
• Shown to have anti-tumor efficacy in the TS603 glioma cell line and to reduce tumor 2-HG production in HT1080 and U87MG cells.
• Caused 50-60% growth inhibition over a treatment period of three weeks with no affect in the growth of IDH1 wild-type glioma xenografts in R132H-IDH1 glioma xenografts.
• Under conditions of near complete 2-HG inhibition, induces demethylation of histone H3K9me3 and expression of genes associated with gliogenic differentiation.
• Useful chemical probe to assess the biological consequences of IDH1 mutations and the potential of IDH1 inhibition for treating IDH1 mutant tumors.
• Requires high doses for in vivo activity, but can be used through oral dosing route.

Product References

Cancer-associated IDH1 mutations produce 2-hydroxyglutarate: L. Dang, et al.; Nature 462, 739 (2009)

Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation: P. Koivunen, et al.; Nature 483, 484 (2012)

IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype: S. Turcan, et al., Nature 483, 479 (2012)

Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism: Z.J. Reitman & H. Yan; J. Natl. Cancer Inst. 102, 932 (2010)

Discovery of the first potent inhibitors of mutant IDH1 that lower tumor 2-HG in vivo: J. Popovici-Muller, et al.; ACS Med. Chem. Lett. 3, 850 (2012)

An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells: D. Rohle, et al.; Science 340, 626 (2013)

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