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
  • 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.) [email protected].
  • 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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