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Research ArticleArticle

Discovery and Characterization of Nonpeptidyl Agonists of the Tissue-Protective Erythropoietin Receptor

James L. Miller, Timothy J. Church, Dmitri Leonoudakis, Karen Lariosa-Willingham, Normand L. Frigon, Connie S. Tettenborn, Jeffrey R. Spencer and Juha Punnonen
Molecular Pharmacology August 2015, 88 (2) 357-367; DOI: https://doi.org/10.1124/mol.115.098400
James L. Miller
STATegics, Inc., Menlo Park, California
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Timothy J. Church
STATegics, Inc., Menlo Park, California
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Dmitri Leonoudakis
STATegics, Inc., Menlo Park, California
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Karen Lariosa-Willingham
STATegics, Inc., Menlo Park, California
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Normand L. Frigon
STATegics, Inc., Menlo Park, California
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Connie S. Tettenborn
STATegics, Inc., Menlo Park, California
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Jeffrey R. Spencer
STATegics, Inc., Menlo Park, California
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Juha Punnonen
STATegics, Inc., Menlo Park, California
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Abstract

Erythropoietin (EPO) and its receptor are expressed in a wide variety of tissues, including the central nervous system. Local expression of both EPO and its receptor is upregulated upon injury or stress and plays a role in tissue homeostasis and cytoprotection. High-dose systemic administration or local injection of recombinant human EPO has demonstrated encouraging results in several models of tissue protection and organ injury, while poor tissue availability of the protein limits its efficacy. Here, we describe the discovery and characterization of the nonpeptidyl compound STS-E412 (2-[2-(4-chlorophenoxy)ethoxy]-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine), which selectively activates the tissue-protective EPO receptor, comprising an EPO receptor subunit (EPOR) and the common β-chain (CD131). STS-E412 triggered EPO receptor phosphorylation in human neuronal cells. STS-E412 also increased phosphorylation of EPOR, CD131, and the EPO-associated signaling molecules JAK2 and AKT in HEK293 transfectants expressing EPOR and CD131. At low nanomolar concentrations, STS-E412 provided EPO-like cytoprotective effects in primary neuronal cells and renal proximal tubular epithelial cells. The receptor selectivity of STS-E412 was confirmed by a lack of phosphorylation of the EPOR/EPOR homodimer, lack of activity in off-target selectivity screening, and lack of functional effects in erythroleukemia cell line TF-1 and CD34+ progenitor cells. Permeability through artificial membranes and Caco-2 cell monolayers in vitro and penetrance across the blood-brain barrier in vivo suggest potential for central nervous system availability of the compound. To our knowledge, STS-E412 is the first nonpeptidyl, selective activator of the tissue-protective EPOR/CD131 receptor. Further evaluation of the potential of STS-E412 in central nervous system diseases and organ protection is warranted.

Footnotes

    • Received February 13, 2015.
    • Accepted May 27, 2015.
  • This work was supported by the Friedreich’s Ataxia Research Alliance, the Michael J. Fox Foundation for Parkinson’s Research, the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant 1R43-DK100140-01], and the Department of Defense ([Grant W81XWH-11-2-0009, DM090012] (U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD 21702-5014 awarding and administering acquisition office). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the U.S. government.

  • dx.doi.org/10.1124/mol.115.098400.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 88 (2)
Molecular Pharmacology
Vol. 88, Issue 2
1 Aug 2015
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Research ArticleArticle

Nonpeptidyl Agonists of the Tissue-Protective EPO Receptor

James L. Miller, Timothy J. Church, Dmitri Leonoudakis, Karen Lariosa-Willingham, Normand L. Frigon, Connie S. Tettenborn, Jeffrey R. Spencer and Juha Punnonen
Molecular Pharmacology August 1, 2015, 88 (2) 357-367; DOI: https://doi.org/10.1124/mol.115.098400

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Research ArticleArticle

Nonpeptidyl Agonists of the Tissue-Protective EPO Receptor

James L. Miller, Timothy J. Church, Dmitri Leonoudakis, Karen Lariosa-Willingham, Normand L. Frigon, Connie S. Tettenborn, Jeffrey R. Spencer and Juha Punnonen
Molecular Pharmacology August 1, 2015, 88 (2) 357-367; DOI: https://doi.org/10.1124/mol.115.098400
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