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Mol Pharmacol. 2018 Dec 19. pii: mol.118.114231. doi: 10.1124/mol.118.114231. [Epub ahead of print]

S29434, a quinone reductase 2 inhibitor: main biochemical and cellular characterization.

Author information

1
Institut de Recherches Servier, Croissy-sur-Seine; jean.boutin@servier.com.
2
Institut Cochin, Paris.
3
Magna Graecia University, Catanzaro.
4
EGIS Pharmaceuticals, Budapest.
5
ICOA, Universite d'Orleans.
6
Institut du Cerveau et de la Moelle epiniere, Paris.
7
St. Francis Xavier University, Antigonish.
8
Pharma-Dev, Universite de Toulouse.
9
EUROFINS-CEREP SA, Celle L'Evescault.
10
Technologie Servier, Orleans.
11
Institut de Recherches Servier, Croissy-sur-Seine.
12
Oxygen Healthcare Pvt Ltd, Ahmedabad.
13
Institut de Recherches Servier, Suresnes.
14
GICC Innovation Moleculaire et Therapeutique, Tours.

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 S29434 (IC50 = 5 to 16 nM) of QR2 at different organizational levels. We provide full detailed syntheses; describe its co-crystallization with and behavior at QR2 on a millisecond timeline; show that it penetrates cell membranes and inhibits QR2-mediated 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 pathological conditions including neurodegenerative diseases.

KEYWORDS:

EPR spectroscopy; Enzyme kinetics; Quinone oxidoreductase; Reactive oxygen species (ROS)

PMID:
30567956
DOI:
10.1124/mol.118.114231
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