Setanaxib (GKT137831) is an Orally Active And Specific NOX1/4 Inhibitor for Cardiovascular Disease Research

NOX1 and NOX4 are two members of the NADPH oxidase family, as well as multiple transmembrane proteins on the cell membrane. NOX1/4 catalyzes oxygen and NADPH into superoxide radicals to participate in REDOX reactions in a range of physiological and pathological processes. NOX1/4 shows pathogenicity but has no obvious spontaneous pathology in inflammation and fibrosis. Specifically, NOX1 is an important regulator of intestinal smooth muscle contraction, gastric acid production, vascular smooth muscle cell proliferation and migration, and other physiological functions. NOX4, on the other hand, regulates intracellular calcium ion concentration and ROS levels. It is also involved in vascular regeneration mechanisms. Therefore, NOX1 or NOX4 inhibitors have the potential to reduce damage and inflammatory responses caused by oxidative stress, especially against cardiovascular diseases. Here, we’ll introduce a NOX1/4 inhibitor, Setanaxib (GKT137831).

Setanaxib is an orally active and dual inhibitor of NOX1/4 with high affinity and selectivity.

Firstly, Setanaxib binds to NOX1 and NOX4 with Ki values of 140 nM and 110 nM, respectively. It (5-20 μM; 24 h or 72 h) inhibits cell profeliration of hypoxia-exposed human pulmonary artery endothelial or smooth muscle cells (HPAECs or HPASMCs). Setanaxib also decreases hypoxia (1% O2)-induced H2O2 release, proliferation, and TGF-β1 expression in cells.

As for in vivo studies, Setanaxib (30 mg/kg, 60 mg/kg; po; once daily for 10 days) inhibits hypoxia-induced increases in TGF-β1 and reductions in PPARγ expression in hypoxic mouse models. Phenotypically, it attenuates right ventricular hypertrophy (RVH) and pulmonary artery wall thickness of mice. Another hand, Setanaxib (60 mg/kg; ig; once daily for 10 days) significantly attenuates liver inflammation and injury in mice of CCl4-induced liver fibrosis models. Moreover, it decreases hepatic MDA levels and suppresses ROS generation in SOD1mu mouse hepatic stellate cells (HSCs).

Above all, Setanaxib is an orally active and selective NOX1/4 inhibitor with anti-reactive oxygen damage properties.


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[3] Teixeira G, et al. Therapeutic potential of NADPH oxidase 1/4 inhibitors. Br J Pharmacol. 2017 Jun;174(12):1647-1669.