Host: The Japanese Society of Toxicology
Name : The 51st Annual Meeting of the Japanese Society of Toxicology
Date : July 03, 2024 - July 05, 2024
Drug repositioning is a strategic approach aimed at discovering new use for approved drugs by exploring their potential for expanded indications. NADPH oxidase (NOX) is an enzyme complex that generates superoxide by transferring one electron from NADPH to molecular oxygen. Among its isoforms, NOX2 stands out as a potential target for inflammatory and thrombotic disorders. In this study, a drug library screening was conducted to identify existing drugs with NOX inhibitory activity. Cell-based assays, specific to NOX1–5, were performed using three different ROS probes such as WST-1, Amplex Red, and coumarin boronic acid. This screening identified LS14 as a potential NOX inhibitor with selectivity for NOX2 over other isoforms. Counter assays confirmed that LS14 is not a non-selective ROS scavenger, and its activity was not attributed to cytotoxicity. In vivo efficacy was assessed using a complete Freund’s adjuvant-induced paw inflammation model and a FeCl3-induced arterial thrombosis model in mice. Oral administration of LS14 effectively reduced paw thickening and ROS formation at a dose of 1 mg/kg, demonstrating comparable efficacy to NOX2 knockout. Additionally, LS14 prolonged vascular occlusion time at the same dose. Moreover, LS14 inhibited collagen-induced platelet aggregation and P-selectin exposure in a concentration-dependent manner. In conclusion, LS14 emerges as a selective NOX2 inhibitor with in vivo efficacy. Further studies hold promise for uncovering additional therapeutic indications for LS14.
