2. Academic Validation
  3. Discovery of GSK2795039, a Novel Small Molecule NADPH Oxidase 2 Inhibitor

Discovery of GSK2795039, a Novel Small Molecule NADPH Oxidase 2 Inhibitor

  • Antioxid Redox Signal. 2015 Aug 10;23(5):358-74. doi: 10.1089/ars.2014.6202.
Kazufumi Hirano 1,  Woei Shin Chen 1,  Adeline L W Chueng 1,  Angela A Dunne 1,  Tamara Seredenina 2,  Aleksandra Filippova 2,  Sumitra Ramachandran 1,  Angela Bridges 3,  Laiq Chaudry 3,  Gary Pettman 3,  Craig Allan 3,  Sarah Duncan 1,  Kiew Ching Lee 1,  Jean Lim 1,  May Thu Ma 1,  Agnes B Ong 1,  Nicole Y Ye 1,  Shabina Nasir 1,  Sri Mulyanidewi 1,  Chiu Cheong Aw 1,  Pamela P Oon 1,  Shihua Liao 4,  Dizheng Li 4,  Douglas G Johns 5,  Neil D Miller 1,  Ceri H Davies 1,  Edward R Browne 1,  Yasuji Matsuoka 1,  Deborah W Chen 1,  Vincent Jaquet 2,  A Richard Rutter 1
Affiliations

Affiliations

  • 1 1 Neural Pathways Discovery Performance Unit, Neurosciences Therapeutic Area, GlaxoSmithKline , Biopolis, Singapore .
  • 2 2 Department of Pathology and Immunology, Medical School, Centre Médical Universitaire, University of Geneva , Geneva, Switzerland .
  • 3 3 Platform Technology & Sciences Department, GlaxoSmithKline , Stevenage, United Kingdom .
  • 4 4 Neuroimmunology Discovery Performance Unit, Neurosciences Therapeutic Area, GlaxoSmithKline , Shanghai, China .
  • 5 5 Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline , King of Prussia, Pennsylvania.
PMID: 26135714 DOI: 10.1089/ars.2014.6202
Abstract

Aims: The NADPH Oxidase (NOX) family of Enzymes catalyzes the formation of Reactive Oxygen Species (ROS). NOX Enzymes not only have a key role in a variety of physiological processes but also contribute to oxidative stress in certain disease states. To date, while numerous small molecule inhibitors have been reported (in particular for NOX2), none have demonstrated inhibitory activity in vivo. As such, there is a need for the identification of improved NOX inhibitors to enable further evaluation of the biological functions of NOX Enzymes in vivo as well as the therapeutic potential of NOX inhibition. In this study, both the in vitro and in vivo pharmacological profiles of GSK2795039, a novel NOX2 Inhibitor, were characterized in comparison with Other published NOX inhibitors.

Results: GSK2795039 inhibited both the formation of ROS and the utilization of the Enzyme substrates, NADPH and oxygen, in a variety of semirecombinant cell-free and cell-based NOX2 assays. It inhibited NOX2 in an NADPH competitive manner and was selective over Other NOX isoforms, Xanthine Oxidase, and endothelial nitric oxide synthase Enzymes. Following systemic administration in mice, GSK2795039 abolished the production of ROS by activated NOX2 Enzyme in a paw inflammation model. Furthermore, GSK2795039 showed activity in a murine model of acute pancreatitis, reducing the levels of serum amylase triggered by systemic injection of cerulein.

Innovation and conclusions: GSK2795039 is a novel NOX2 Inhibitor that is the first small molecule to demonstrate inhibition of the NOX2 Enzyme in vivo.

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