101. S29434, a Quinone Reductase 2 Inhibitor: Main Biochemical and Cellular Characterization
- Author
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Boutin, Jean A., Bouillaud, Frederic, Janda, Elzbieta, Gacsalyi, István, Guillaumet, Gérald, Hirsch, Etienne C., Kane, Daniel A., Nepveu, Francoise, Reybier, Karine, Dupuis, Philippe, Bertrand, Marc, Chhour, Monivan, Le Diguarher, Thierry, Antoine, Mathias, Brebner, Karen, Da Costa, Hervé, Ducrot, Pierre, Giganti, Adeline, Goswami, Vishalgiri, Guedouari, Hala, Michel, Patrick P., Patel, Aakash, Paysant, Jérôme, Stojko, Johann, Viaud-Massuard, Marie-Claude, and Ferry, Gilles
- Abstract
Quinone reductase 2 (QR2, E.C. 1.10.5.1) is an enzyme with a feature that has attracted attention for several decades: in standard conditions, instead of recognizing NAD(P)H as an electron donor, it recognizes putative metabolites of NADH, such as N-methyl- and N-ribosyl-dihydronicotinamide. QR2 has been particularly associated with reactive oxygen species and memory, strongly suggesting a link among QR2 (as a possible key element in pro-oxidation), autophagy, and neurodegeneration. In molecular and cellular pharmacology, understanding physiopathological associations can be difficult because of a lack of specific and powerful tools. Here, we present a thorough description of the potent, nanomolar inhibitor [2-(2-methoxy-5H-1,4b,9-triaza(indeno[2,1-a]inden-10-yl)ethyl]-2-furamide (S29434 or NMDPEF; IC50= 5–16 nM) of QR2 at different organizational levels. We provide full detailed syntheses, describe its cocrystallization with and behavior at QR2 on a millisecond timeline, show that it penetrates cell membranes and inhibits QR2-mediated reactive oxygen species (ROS) production within the 100 nM range, and describe its actions in several in vivo models and lack of actions in various ROS-producing systems. The inhibitor is fairly stable in vivo, penetrates cells, specifically inhibits QR2, and shows activities that suggest a key role for this enzyme in different pathologic conditions, including neurodegenerative diseases.
- Published
- 2019
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