The antiporter system xc– is a sodium independent amino acid transporter that imports extracellular cystine in exchange for exporting intracellular glutamate(1). Given the key role of microglia in neuroinflammation, system xc– up-regulation in activated microglia has been implicated in the pathogenesis of many neurodegenerative disorders wherein excess glutamate is presumed pathogenic including Alzheimer’s disease(2), Parkinson’s disease(3), epilepsy(4), HIV-associated neurocognitive disorders (HAND)(5), and multiple sclerosis(6). In collaboration with Eisai, we identified new lead system xc– inhibitors from the newly developed HTS screening assay(7). Our program is currently engaged in in the development of brain penetrable system xc– inhibitors as novel therapeutic agents for the treatment of neuroinflammatory disorders.
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5. Gupta S, Knight AG, Gupta S, Knapp PE, Hauser KF, Keller JN, Bruce-Keller AJ. HIV-Tat elicits microglial glutamate release: role of NAPDH oxidase and the cystine-glutamate antiporter. Neurosci Lett. 2010;485(3):233-6. [PubMed]
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7. Thomas AG, Sattler R, Tendyke K, Loiacono KA, Hansen H, Sahni V, Hashizume Y, Rojas C, Slusher BS. High-Throughput Assay Development for Cystine-Glutamate Antiporter (xc-) Highlights Faster Cystine Uptake than Glutamate Release in Glioma Cells. PLoS One. 2015;10(8):e0127785. [PubMed]