Johns Hopkins Drug Discovery - Projects - Cystine/Glutamate Antiporter
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Cystine/Glutamate Antiporter

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.


1. Lewerenz J, Hewett SJ, Huang Y, Lambros M, Gout PW, Kalivas PW, Massie A, Smolders I, Methner A, Pergande M, Smith SB, Ganapathy V, and Maher P.  “The cysteine/glutamate antiporter system x(c)(-) in health and disease: from molecular mechanisms to novel therapeutic opportunities.”  Antioxid Redox Signal, 2013, Feb 10;18, 522-555 [PubMed]

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]

5. Press Release 2010, Brain Science Institute Announces License Agreement To Develop new Treatments for Neurological Disease

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]