Anti-Myeloma Activity of a Novel Glutaminase Inhibitor CB-839

Background and Rationale: Cancer cells possess different metabolic requirements than normal cells, such as increased fatty acid synthesis and increased rates of glutamine metabolism, which facilitate their growth and survival. Glutamine is one of the key metabolites required by different cancer cell types for their survival. It is a precursor for α-keto glutarate (αKG) of tricarboxylic acid cycle. Intracellular glutamine is metabolized by a biochemical process glutaminolysis: glutamine is converted to glutamate by glutaminase (GLS), followed by glutamate conversion to αKG by glutamate dehydrogenase (GDH). Three mammalian GLS have been identified: the Liver-type (LGA or GLS2), the Kidney-type (KGA) and Glutaminase C (GAC). Elevated GAC mRNA levels have been detected in gliomas, colorectal carcinomas, adenomas and breast tumor cell lines. GLS activity is linked to tumor growth, since its inhibition by small molecule inhibitors or siRNA knockdown suppresses tumor growth in solid tumors. Elevated glutaminolysis confers drug resistance. These findings suggest that targeting GLS activity inhibits oncogenic transformation and overcomes drug resistance. Here we evaluated anti-MM activity of CB-839, a novel potent orally bioavailable inhibitor of both KGA and GAC splice variants of glutaminase.