The overall aim of this proposal is to identify small molecule inhibitors of glutaminase through high throughput screening (HTS) of the NIH chemical library. Glutaminase has been identified as a target for the treatment of cMyc-expressing cancers where the up-regulated enzyme has recently been shown to play a critical metabolic role promoting cancer cell growth. Glutaminase has also recently been shown to be up-regulated in activated macrophages/microglia and its inhibition limits glutamate release and provides neuroprotection in inflammatory neurological disorders such as HIV1-associated dementia and multiple sclerosis. To date there are no known potent and selective glutaminase inhibitors available. We propose to screen the NIH chemical library to obtain "hits" that could be used as tool molecules to further study the pharmacology of this target as well as serve as leads for further chemical optimization into drug-like inhibitors for clinical development.
Glutaminase has recently been shown to be up-regulated in cancer cells and activated microglia in inflammatory neurological disorders such as HIV1-associated dementia and multiple sclerosis. Genetic approaches which decrease glutaminase have been shown to inhibit cancer cell proliferation and provide neuroprotection. To date, however, there are no selective small molecule inhibitors of this enzyme. Identification of new glutaminase inhibitors would provide a novel therapeutic strategy for these diseases.
|Saylor, Deanna; Dickens, Alex M; Sacktor, Ned et al. (2016) HIV-associated neurocognitive disorder--pathogenesis and prospects for treatment. Nat Rev Neurol 12:234-48|
|Elgogary, Amira; Xu, Qingguo; Poore, Brad et al. (2016) Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer. Proc Natl Acad Sci U S A 113:E5328-36|
|Alt, Jesse; Potter, Michelle C; Rojas, Camilo et al. (2015) Bioanalysis of 6-diazo-5-oxo-l-norleucine in plasma and brain by ultra-performance liquid chromatography mass spectrometry. Anal Biochem 474:28-34|
|Potter, Michelle C; Baxter, Victoria K; Mathey, Robert W et al. (2015) Neurological sequelae induced by alphavirus infection of the CNS are attenuated by treatment with the glutamine antagonist 6-diazo-5-oxo-l-norleucine. J Neurovirol 21:159-73|
|Thomas, Ajit G; O'Driscoll, Cliona M; Bressler, Joseph et al. (2014) Small molecule glutaminase inhibitors block glutamate release from stimulated microglia. Biochem Biophys Res Commun 443:32-6|
|Thomas, Ajit G; Rojas, Camilo; Tanega, Cordelle et al. (2013) Kinetic characterization of ebselen, chelerythrine and apomorphine as glutaminase inhibitors. Biochem Biophys Res Commun 438:243-8|
|Shukla, Krupa; Ferraris, Dana V; Thomas, Ajit G et al. (2012) Design, synthesis, and pharmacological evaluation of bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3 (BPTES) analogs as glutaminase inhibitors. J Med Chem 55:10551-63|