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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Characterization of the Potent, Selective Nrf2 Activator, 3-(Pyridin-3-Ylsulfonyl)-5-(Trifluoromethyl)-2H-Chromen-2-One, in Cellular and In Vivo Models of Pulmonary Oxidative Stress

John G. Yonchuk, Joseph P. Foley, Brian J. Bolognese, Gregory Logan, William E. Wixted, Jen-Pyng Kou, Diana G. Chalupowicz, Heidi G. Feldser, Yolanda Sanchez, Hong Nie, James F. Callahan, Jeffrey K. Kerns and Patricia L. Podolin
Journal of Pharmacology and Experimental Therapeutics October 2017, 363 (1) 114-125; DOI: https://doi.org/10.1124/jpet.117.241794
John G. Yonchuk
Stress and Repair Discovery Performance Unit, Respiratory Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania
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Joseph P. Foley
Stress and Repair Discovery Performance Unit, Respiratory Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania
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Brian J. Bolognese
Stress and Repair Discovery Performance Unit, Respiratory Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania
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Gregory Logan
Stress and Repair Discovery Performance Unit, Respiratory Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania
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William E. Wixted
Stress and Repair Discovery Performance Unit, Respiratory Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania
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Jen-Pyng Kou
Stress and Repair Discovery Performance Unit, Respiratory Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania
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Diana G. Chalupowicz
Stress and Repair Discovery Performance Unit, Respiratory Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania
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Heidi G. Feldser
Stress and Repair Discovery Performance Unit, Respiratory Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania
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Yolanda Sanchez
Stress and Repair Discovery Performance Unit, Respiratory Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania
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Hong Nie
Stress and Repair Discovery Performance Unit, Respiratory Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania
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James F. Callahan
Stress and Repair Discovery Performance Unit, Respiratory Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania
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Jeffrey K. Kerns
Stress and Repair Discovery Performance Unit, Respiratory Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania
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Patricia L. Podolin
Stress and Repair Discovery Performance Unit, Respiratory Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania
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Abstract

Nuclear factor (erythroid-derived 2)–like 2 (Nrf2) is a key regulator of oxidative stress and cellular repair and can be activated through inhibition of its cytoplasmic repressor, Kelch-like ECH-associated protein 1 (Keap1). Several small molecule disrupters of the Nrf2-Keap1 complex have recently been tested and/or approved for human therapeutic use but lack either potency or selectivity. The main goal of our work was to develop a potent, selective activator of NRF2 as protection against oxidative stress. In human bronchial epithelial cells, our Nrf2 activator, 3-(pyridin-3-ylsulfonyl)-5-(trifluoromethyl)-2H-chromen-2-one (PSTC), induced Nrf2 nuclear translocation, Nrf2-regulated gene expression, and downstream signaling events, including induction of NAD(P)H:quinone oxidoreductase 1 (NQO1) enzyme activity and heme oxygenase-1 protein expression, in an Nrf2-dependent manner. As a marker of subsequent functional activity, PSTC restored oxidant (tert-butyl hydroperoxide)–induced glutathione depletion. The compound’s engagement of the Nrf2 signaling pathway translated to an in vivo setting, with induction of Nrf2-regulated gene expression and NQO1 enzyme activity, as well as restoration of oxidant (ozone)–induced glutathione depletion, occurring in the lungs of PSTC-treated rodents. Under disease conditions, PSTC engaged its target, inducing the expression of Nrf2-regulated genes in human bronchial epithelial cells derived from patients with chronic obstructive pulmonary disease, as well as in the lungs of cigarette smoke–exposed mice. Subsequent to the latter, a dose-dependent inhibition of cigarette smoke–induced pulmonary inflammation was observed. Finally, in contrast with bardoxolone methyl and sulforaphane, PSTC did not inhibit interleukin-1β–induced nuclear factor-κB translocation or insulin-induced S6 phosphorylation in human cells, emphasizing the on-target activity of this compound. In summary, we characterize a potent, selective Nrf2 activator that offers protection against pulmonary oxidative stress in several cellular and in vivo models.

Footnotes

    • Received May 17, 2017.
    • Accepted August 2, 2017.
  • https://doi.org/10.1124/jpet.117.241794.

  • Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 363 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 363, Issue 1
1 Oct 2017
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Characterization of the Potent, Selective Nrf2 Activator, 3-(Pyridin-3-Ylsulfonyl)-5-(Trifluoromethyl)-2H-Chromen-2-One, in Cellular and In Vivo Models of Pulmonary Oxidative Stress
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Nrf2 Activator PSTC in Oxidative Stress Models

John G. Yonchuk, Joseph P. Foley, Brian J. Bolognese, Gregory Logan, William E. Wixted, Jen-Pyng Kou, Diana G. Chalupowicz, Heidi G. Feldser, Yolanda Sanchez, Hong Nie, James F. Callahan, Jeffrey K. Kerns and Patricia L. Podolin
Journal of Pharmacology and Experimental Therapeutics October 1, 2017, 363 (1) 114-125; DOI: https://doi.org/10.1124/jpet.117.241794

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Nrf2 Activator PSTC in Oxidative Stress Models

John G. Yonchuk, Joseph P. Foley, Brian J. Bolognese, Gregory Logan, William E. Wixted, Jen-Pyng Kou, Diana G. Chalupowicz, Heidi G. Feldser, Yolanda Sanchez, Hong Nie, James F. Callahan, Jeffrey K. Kerns and Patricia L. Podolin
Journal of Pharmacology and Experimental Therapeutics October 1, 2017, 363 (1) 114-125; DOI: https://doi.org/10.1124/jpet.117.241794
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