AGI-5198 (IDH-C35) is a potent and selective isocitrate dehydrogenase 1 (IDH1) inhibitor specifically against R132H/C mutants (mIDH1) with IC50 at 100 nM range. AGI-5198 does not inhibit wild-type IDH1 or any of the examined IDH2 isoforms (IC50 > 100 µM).[1] AGI-5198 inhibits R-2-hydroxyglutarate (R-2HG) production by mIDH1. AGI-5198 also induces demethylation of histone H3K9me3 and expression of genes associated with gliogenic differentiation.

In both in vitro and in vivo studies, AGI-5198 inhibited the growth of glioma cells carrying mutated but not wild type IDH1, yet with no appreciable changes in genome-wide DNA methylation. These data suggest that mIDH1 may promote glioma growth through mechanisms beyond its well-characterized epigenetic effects. AGI-5198 could serve as a very useful chemical tool to probe the mechanism and treatment of mIDH1-carrying tumors