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

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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https://www.hal.inserm.fr/inserm-02334766
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Submitted on : Sunday, October 27, 2019 - 3:48:50 PM
Last modification on : Tuesday, May 4, 2021 - 3:25:40 PM
Long-term archiving on: : Tuesday, January 28, 2020 - 12:23:27 PM

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Jean Boutin, Frédéric Bouillaud, Elzbieta Janda, István Gacsalyi, Gerald Guillaumet, et al.. S29434, a Quinone Reductase 2 Inhibitor: Main Biochemical and Cellular Characterization. Molecular Pharmacology, American Society for Pharmacology and Experimental Therapeutics, 2019, 95 (3), pp.269-285. ⟨10.1124/mol.118.114231⟩. ⟨inserm-02334766⟩

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