Cancer esearch apeutics , Targets , and Chemical Biology bition of Glutaminase Preferentially Slows Growth of R ma Cells with Mutant IDH 1

nloaded ation at the R132 residue of isocitrate dehydrogenase 1 (IDH1), frequently found in gliomas and acute genous leukemia, creates a neoenzyme that produces 2-hydroxyglutarate (2-HG) from α-ketoglutarate ). We sought to therapeutically exploit this neoreaction in mutant IDH1 cells that require α-KG derived glutamine. Glutamine is converted to glutamate by glutaminase and further metabolized to α-KG. ore, we inhibited glutaminase with siRNA or the small molecule inhibitor bis-2-(5-phenylacetamidohiadiazol-2-yl)ethyl sulfide (BPTES) and found slowed growth of glioblastoma cells expressing mutant compared with those expressing wild-type IDH1. Growth suppression of mutant IDH1 cells by BPTES scued by adding exogenous α-KG. BPTES inhibited glutaminase activity, lowered glutamate and α-KG and increased glycolytic intermediates while leaving total 2-HG levels unaffected. The ability to selectively slow growth in cells with IDH1 mutations by inhibiting glutaminase suggests a unique reprogramming of intermediary metabolism and a potential therapeutic strategy. Cancer Res; 70(22); OF1–7. ©2010 AACR.