Structural Reassignment of Compound 968, an Allosteric Glutaminase Inhibitor

Many cancer cells require extracellular glutamine to meet the energetic, biosynthetic, and redox demands of the proliferative state. Glutaminase enzymes catalyze the hydrolysis of glutamine to glutamate, which supports the biosynthesis of amino acids, lipids, and glutathione and can also be oxidatively deaminated to α-ketoglutarate and enter the citric acid cycle. The “glutamine addiction” of cancer cells has made glutaminase an attractive anticancer drug target. Compound 968 is a glutaminase inhibitor that is widely used to probe cancer cells’ dependance on glutaminase activity. Here we show by NMR spectroscopy and X-ray crystallography that the benzo[c]phenanthridine structure of compound 968 is incorrect; its true structure is the isomeric benzo[c]acridine. The structural reassignment of 968 will aid the medicinal chemistry development of this important compound.