Development of an improved and specific inhibitor of NADPH oxidase 2 to treat traumatic brain injury

• DOI: 10.1016/j.redox.2023.102611
• Publication Date: 2023-01-18T19:02:23Z
• Authors: Hannah Mason; Ganesha Rai; Arina Kozyr; Nathaniel De Jonge; Emily Gliniewicz; Lars J. Berg; Gal Wald; Cayce Dorrier; Mark J. Henderson; Alexey Zakharov; Tristan Dyson; John Audley; Anthony M. Pettinato; Elias Carvalho Pa...; Pranav Shah; Xin Xu; Thomas L. Leto; Anton Simeonov; Kol A. Zarember; Dorian B. McGavern; John I. Gallin
• Keywords: NOX4; NOX1

NADPH oxidases (NOX's), and the reactive oxygen species (ROS) they produce, play an important role in host defense, thyroid hormone synthesis, apoptosis, gene regulation, angiogenesis other processes. However, overproduction of ROS by these enzymes is associated with cardiovascular disease, fibrosis, traumatic brain injury (TBI) diseases. Structural similarities between NOX's have complicated development specific inhibitors. Here, we report NCATS-SM7270, a small molecule optimized from GSK2795039, that inhibited NOX2 primary human mouse granulocytes. NCATS-SM7270 specifically had reduced inhibitory activity against xanthine oxidase vitro. We also studied several NOX isoforms during mild TBI (mTBI) demonstrated and, to lesser extent, NOX1 deficient mice are protected mTBI pathology, whereas exacerbated NOX4 knockouts. Given pathogenic played mTBI, treated transcranially after revealed dose-dependent reduction induced cortical cell death. This inhibitor partially reversed damage observed following mTBI. These data demonstrate improved capable protecting NOX2-dependent death