1. Academic Validation
  2. S29434, a Quinone Reductase 2 Inhibitor: Main Biochemical and Cellular Characterization

S29434, a Quinone Reductase 2 Inhibitor: Main Biochemical and Cellular Characterization

  • Mol Pharmacol. 2019 Mar;95(3):269-285. doi: 10.1124/mol.118.114231.
Jean A Boutin 1 Frederic Bouillaud 2 Elzbieta Janda 2 István Gacsalyi 2 Gérald Guillaumet 2 Etienne C Hirsch 2 Daniel A Kane 2 Françoise Nepveu 2 Karine Reybier 2 Philippe Dupuis 2 Marc Bertrand 2 Monivan Chhour 2 Thierry Le Diguarher 2 Mathias Antoine 2 Karen Brebner 2 Hervé Da Costa 2 Pierre Ducrot 2 Adeline Giganti 2 Vishalgiri Goswami 2 Hala Guedouari 2 Patrick P Michel 2 Aakash Patel 2 Jérôme Paysant 2 Johann Stojko 2 Marie-Claude Viaud-Massuard 2 Gilles Ferry 2
Affiliations

Affiliations

  • 1 Pôle d'Expertise Biotechnologie, Chimie & Biologie, Institut de Recherches SERVIER, Croissy-sur-Seine, France (J.A.B., M.A., Pi.D., A.G., J.S., G.F.); Institut Cochin, INSERM U1016, CNRS-UMR8104, Université Paris Descartes, Paris, France (F.B., H.G.); Department of Health Sciences, Magna Graecia University, Catanzaro, Italy (E.J.); Egis Pharmaceuticals PLC, Budapest, Hungary (I.G.); Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans, UMR CNRS 7311, Orléans Cedex 2, France (G.G., H.D.C.); Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université, Paris, France (E.C.H., P.P.M.); Departments of Human Kinetics (D.A.K.) and Psychology (K.B.), St. Francis Xavier University, Antigonish, Nova Scotia, Canada; UMR 152 Pharma-Dev, Université de Toulouse, IRD, UPS, Toulouse, France (F.N., K.R., M.C.); EUROFINS-CEREP SA, Celle L'Evescault, France (Ph.D.); Technologie Servier, Orléans, France (M.B., T.L.D.); CNRS-UMR 7292, GICC Innovation Moléculaire et Thérapeutique, Université de Tours, Tours, France (H.D.C., M.-C.V.-M.); Oxygen Healthcare Pvt Ltd, Ahmedabad, Gujarat, India (V.G., A.P.); and Pôle d'Innovation Thérapeutique de Cardiologie, Institut de Recherches SERVIER, Suresnes, France (J.P.) jean.boutin@servier.com.
  • 2 Pôle d'Expertise Biotechnologie, Chimie & Biologie, Institut de Recherches SERVIER, Croissy-sur-Seine, France (J.A.B., M.A., Pi.D., A.G., J.S., G.F.); Institut Cochin, INSERM U1016, CNRS-UMR8104, Université Paris Descartes, Paris, France (F.B., H.G.); Department of Health Sciences, Magna Graecia University, Catanzaro, Italy (E.J.); Egis Pharmaceuticals PLC, Budapest, Hungary (I.G.); Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans, UMR CNRS 7311, Orléans Cedex 2, France (G.G., H.D.C.); Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université, Paris, France (E.C.H., P.P.M.); Departments of Human Kinetics (D.A.K.) and Psychology (K.B.), St. Francis Xavier University, Antigonish, Nova Scotia, Canada; UMR 152 Pharma-Dev, Université de Toulouse, IRD, UPS, Toulouse, France (F.N., K.R., M.C.); EUROFINS-CEREP SA, Celle L'Evescault, France (Ph.D.); Technologie Servier, Orléans, France (M.B., T.L.D.); CNRS-UMR 7292, GICC Innovation Moléculaire et Thérapeutique, Université de Tours, Tours, France (H.D.C., M.-C.V.-M.); Oxygen Healthcare Pvt Ltd, Ahmedabad, Gujarat, India (V.G., A.P.); and Pôle d'Innovation Thérapeutique de Cardiologie, Institut de Recherches SERVIER, Suresnes, France (J.P.).
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.

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