The antiporter system xc– is a sodium independent amino acid transporter that imports extracellular cystine in exchange for exporting intracellular glutamate1. Given the key role of microglia in neuroinflammation, system xc– up-regulation in activated microglia has been implicated in the pathogenesis of oncological2, 3 and neurological disorders4 wherein excess glutamate is presumed pathogenic. In collaboration with Eisai Pharmaceuticals5, we developed the first HTS screening assay6, carried out a screen of their large diverse chemical library and identified new lead system xc– inhibitors. Our program is currently engaged in in the development of system xc– inhibitors as novel therapeutic agents for the treatment of oncological and neuroinflammatory disorders.
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2. Lo m, Wang YZ and Gout PW. “The x(c)- cysteine/glutamate antiporter: a potential target for therapy of cancer and other diseases.” J Cell Physiol, 2008, Jun;215(3) 593-602 [PubMed]
3. Robert SM, Buckingham SC, Campbell SL, Robel S, Holt KT, Ogunrinu-Babarinde T, Warren PP, White DM, Reid MA, Eschbacher JM, Berens ME, Lahti AC, Nabors LB and Sontheimer H. “SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma.” Sci Transl Med, 2015 May, 27;7(289) [PubMed]
4. Bridges R, Lutgen V, Lobner D and Baker DA. “Thinking outside the cleft to understand synaptic activity: contribution of the cysteine-glutamate antiporter (System xc-) to normal and pathological glutamatergic signaling.” Pharmacol Rev, 2012, Jul;64(3):780-802 [PubMed]
6. 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) [PubMed]