GKT137831

GKT137831, an orally dual NADPH oxidase 1/4 (NOX1/NOX4) inhibitor with potency in the submicromolar range, could prevent oxidative stress in human aortic endothelial cells induced by hyperglycemia and attenuate the development of atherosclerosis in diabetic mice^[1-2]. GKT137831 does not affect NOX2-mediated phagocyte function^[3].

In vitro, monolayers of Human pulmonary artery smooth muscle cells (HPASMCs) were propagated in culture and placed in hypoxic conditions for 72 hours. Treatment with graded concentrations of GKT137831 (0, 0.1, 5, 20μM) during the last 24 hours of hypoxia exposure attenuated cell proliferation in HPASMCs in a dose-dependent manner, while administration of GKT137831 throughout the 72 hours of hypoxia attenuated HPASMC proliferation at the 20μM concentration^[4]. In primary neonatal rat cardiomyocytes (NRCMs), pretreatment with GKT137831 (5μmol/L, 1h) before Doxorubicin (DOX) treatment attenuated DOX-induced apoptosis^[5].

In vivo, in C57BL/6J-background CCl₄-induced liver fibrosis WT and superoxide dismutase 1 (SOD1) G37R mutant (SOD1mu) mice, after once-daily intragastric administration of 60mg/kg GKT137831 during the latter half of CCl₄ treatment, GKT137831 attenuated liver fibrosis and ROS production in both SOD1mu and WT mice, as well as messenger RNA expression of fibrotic and NOX genes^[6]. In Sprague Dawley rats subjected to the AAC-induced hypertensive model, oral gavage administration of GKT137831 (30mg/kg) markedly reduced the ratio of heart weight to body weight (HW/BW), the ratio of left ventricular weight to body weight (LVW /BW), and myocyte cross-sectional area in AAC-induced hypertensive rats^[7].

References:
[1] Dong Y, Zhang Y, Li F, et al. GKT137831 in combination with adipose-derived stem cells alleviates high glucose-induced inflammaging and improves diabetic wound healing. J Leukoc Biol. 2024;115(5):882-892.
[2] Demircan MB, Mgbecheta PC, Kresinsky A, et al. Combined Activity of the Redox-Modulating Compound Setanaxib (GKT137831) with Cytotoxic Agents in the Killing of Acute Myeloid Leukemia Cells. Antioxidants (Basel). 2022;11(3):513.
[3] Gray SP, Jha JC, Kennedy K, et al. Combined NOX1/4 inhibition with GKT137831 in mice provides dose-dependent reno- and atheroprotection even in established micro- and macrovascular disease. Diabetologia. 2017;60(5):927-937.
[4] Green DE, Murphy TC, Kang BY, et al. The Nox4 inhibitor GKT137831 attenuates hypoxia-induced pulmonary vascular cell proliferation. Am J Respir Cell Mol Biol. 2012;47(5):718-726. 
[5] Zheng H, Xu N, Zhang Z, et al. Setanaxib (GKT137831) Ameliorates Doxorubicin-Induced Cardiotoxicity by Inhibiting the NOX1/NOX4/Reactive Oxygen Species/MAPK Pathway. Front Pharmacol. 2022;13:823975.
[6] Aoyama T, Paik YH, Watanabe S, et al. Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent. Hepatology. 2012;56(6):2316-2327.
[7] Zeng SY, Yang L, Yan QJ, et al. Nox1/4 dual inhibitor GKT137831 attenuates hypertensive cardiac remodelling associating with the inhibition of ADAM17-dependent proinflammatory cytokines-induced signalling pathways in the rats with abdominal artery constriction. Biomed Pharmacother. 2019;109:1907-1914.

GKT137831是一种口服有效的双重NADPH氧化酶1/4（NOX1/NOX4）抑制剂，活性处于亚微摩尔范围，可预防高糖诱导的人主动脉内皮细胞氧化应激，并减轻糖尿病小鼠的动脉粥样硬化进展^[1-2]。该化合物不影响NOX2介导的吞噬细胞功能^[3]。

在体外，体外培养的人肺动脉平滑肌细胞（HPASMCs）单层于缺氧条件下培养72小时。在缺氧暴露的最后24小时内给予梯度浓度GKT137831（0、0.1、5、20μM），可呈剂量依赖性抑制HPASMC增殖；而在整个72小时缺氧期间持续给予GKT137831，20μM的GKT137831亦可抑制HPASMC增殖^[4]。在原代新生大鼠心肌细胞（NRCMs）中，先用GKT137831（5μmol/L；1h）预处理再给予阿霉素（DOX），可显著减轻DOX诱导的细胞凋亡^[5]。

在体内，CCl₄诱导的肝纤维化野生型（WT）和超氧化物歧化酶1（SOD1）G37R突变（SOD1mu）C57BL/6J小鼠在CCl₄处理后期每日一次经口灌胃给予60mg/kg的GKT137831，GKT137831在SOD1mu和WT小鼠中均减轻了肝纤维化程度及ROS生成，并下调了纤维化基因及NOX基因的mRNA表达^[6]。在腹主动脉缩窄（AAC）诱导的高血压Sprague Dawley大鼠中，经口灌胃给予GKT137831（30mg/kg）显著降低了心脏重量/体重比（HW/BW）、左心室重量/体重比（LVW/BW）及心肌细胞横截面积^[7]。