TY - JOUR T1 - S29434, a Quinone Reductase 2 Inhibitor: Main Biochemical and Cellular Characterization JF - Molecular Pharmacology JO - Mol Pharmacol SP - 269 LP - 285 DO - 10.1124/mol.118.114231 VL - 95 IS - 3 AU - Jean A. Boutin AU - Frederic Bouillaud AU - Elzbieta Janda AU - István Gacsalyi AU - Gérald Guillaumet AU - Etienne C. Hirsch AU - Daniel A. Kane AU - Françoise Nepveu AU - Karine Reybier AU - Philippe Dupuis AU - Marc Bertrand AU - Monivan Chhour AU - Thierry Le Diguarher AU - Mathias Antoine AU - Karen Brebner AU - Hervé Da Costa AU - Pierre Ducrot AU - Adeline Giganti AU - Vishalgiri Goswami AU - Hala Guedouari AU - Patrick P. Michel AU - Aakash Patel AU - Jérôme Paysant AU - Johann Stojko AU - Marie-Claude Viaud-Massuard AU - Gilles Ferry Y1 - 2019/03/01 UR - http://molpharm.aspetjournals.org/content/95/3/269.abstract N2 - 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. ER -