PT - JOURNAL ARTICLE AU - John G. Yonchuk AU - Joseph P. Foley AU - Brian J. Bolognese AU - Gregory Logan AU - William E. Wixted AU - Jen-Pyng Kou AU - Diana G. Chalupowicz AU - Heidi G. Feldser AU - Yolanda Sanchez AU - Hong Nie AU - James F. Callahan AU - Jeffrey K. Kerns AU - Patricia L. Podolin TI - Characterization of the Potent, Selective Nrf2 Activator, 3-(Pyridin-3-Ylsulfonyl)-5-(Trifluoromethyl)-2<em>H</em>-Chromen-2-One, in Cellular and In Vivo Models of Pulmonary Oxidative Stress AID - 10.1124/jpet.117.241794 DP - 2017 Oct 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 114--125 VI - 363 IP - 1 4099 - http://jpet.aspetjournals.org/content/363/1/114.short 4100 - http://jpet.aspetjournals.org/content/363/1/114.full SO - J Pharmacol Exp Ther2017 Oct 01; 363 AB - 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.