Glutaminase catalyzes the hydrolysis of glutamine to glutamate and plays a central role in the proliferation of neoplastic cells via glutaminolysis, as well as in the generation of excitotoxic glutamate in central nervous system disorders such as HIV-associated dementia (HAD) and multiple sclerosis. Both glutaminase siRNA and glutaminase inhibition have been shown to be effective in in vitro models of cancer and HAD, suggesting a potential role for small molecule glutaminase inhibitors. However, there are no potent, selective inhibitors of glutaminase currently available. The two prototypical glutaminase inhibitors, BPTES and DON, are either insoluble or non-specific. In a search for more drug-like glutaminase inhibitors, we conducted a screen of 1280 in vivo active drugs (Library of Pharmacologically Active Compounds (LOPAC(1280))) and identified ebselen, chelerythrine and (R)-apomorphine. The newly identified inhibitors exhibited 10 to 1500-fold greater affinities than DON and BPTES and over 100-fold increased efficiency of inhibition. Although non-selective, it is noteworthy that the affinity of ebselen for glutaminase is more potent than any other activity yet described. It is possible that the previously reported biological activity seen with these compounds is due, in part, to glutaminase inhibition. Ebselen, chelerythrine and apomorphine complement the armamentarium of compounds to explore the role of glutaminase in disease.
Keywords: 1,2-dimethoxy-N-methyl[1,3]benzodioxolo[5,6-c]phenanthridinium; 13-methyl-[1,3]-benzodioxolo[5,6-c]-1,3-dioxolo[4,5-i]phenanthridinium; 2,3-dimethoxy-N-methyl[1,3]benzodioxolo[5,6-c]phenanthridinium; 2-phenyl-1,2-benzisoselenazol-3[2H]-one; 5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo[de,g]quinoline-10,11-diol; 5,6-dihydro-9,10-dimethoxy-benzo[g]-[1,3]benzodioxolo[5,6-a]quinolizinium; 6-diazo-5-oxo-l-norleucine; Apomorphine; BPTES; Berberine; CNS; Cancer; Chelerythrine; DON; Ebselen; GAC; GLS; Glutamate; Glutaminase; Glutamine; HIV; HIV-associated dementia (HAD); HRP; KGA; Kinetics; LGA; Nitidine; Norsanguinarine; Sanguinarine; [1,3]-benzodioxolo[5,6-c]-1,3-dioxolo[4,5-i]phenanthridine; bis-2-(5-phenylacetimido-1,2,4-thiadiazol-2-yl)ethyl sulfide; c-type glutaminase; central nervous system; glutaminase; horse radish peroxidase; human immunodeficiency virus; kidney-type glutaminase; liver-type glutaminase.
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