2. Academic Validation
  3. 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.).
PMID: 30567956 DOI: 10.1124/mol.118.114231
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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