An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells

• DOI: 10.1126/science.1236062
• Publication Date: 2013-04-05T03:56:07Z
• Authors: Dan Rohle; Janeta Popovici-M...; Nicolaos Palaskas; Sevin Turcan; Christian Grommes; Carl Campos; Jennifer Tsoi; Owen Clark; Barbara Oldrini; Evangelia Komisop...; 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
• Keywords: Isocitrate dehydrogenase; Wild type

The recent discovery of mutations in metabolic enzymes has rekindled interest harnessing the altered metabolism cancer cells for therapy. One potential drug target is isocitrate dehydrogenase 1 (IDH1), which mutated multiple human cancers. Here, we examine role mutant IDH1 fully transformed with endogenous mutations. A selective R132H-IDH1 inhibitor (AGI-5198) identified through a high-throughput screen blocked, dose-dependent manner, ability enzyme (mIDH1) to produce R-2-hydroxyglutarate (R-2HG). Under conditions near-complete R-2HG inhibition, mIDH1 induced demethylation histone H3K9me3 and expression genes associated gliogenic differentiation. Blockade impaired growth IDH1-mutant--but not IDH1-wild-type--glioma without appreciable changes genome-wide DNA methylation. These data suggest that may promote glioma mechanisms beyond its well-characterized epigenetic effects.