Discovery of GSK2795039, a Novel Small Molecule NADPH Oxidase 2 Inhibitor
Discovery of GSK2795039, a Novel Small Molecule NADPH Oxidase 2 Inhibitor
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DOI：
10.1089/ars.2014.6202
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发表时间：
2015-08-10
影响因子：
6.6
通讯作者：
Rutter, A. Richard
中科院分区：
文献类型：
--
作者：
Hirano, Kazufumi;Chen, Woei Shin;Rutter, A. Richard
目的：NADPH氧化酶（NOX）家族的酶催化活性氧（ROS）的形成。NOX酶不仅在各种生理过程中起关键作用，而且在某些疾病状态下也有助于氧化应激。迄今为止，虽然已经报道了许多小分子抑制剂（特别是对于N 0X 2），但是没有一种在体内表现出抑制活性。因此，需要鉴定改进的NOX抑制剂以能够进一步评价NOX酶的体内生物学功能以及NOX抑制的治疗潜力。在这项研究中，无论是在体外和体内的药理学特性的GSK 2795039，一种新的NOX 2抑制剂，其特征在于与其他已发表的NOX抑制剂相比。结果如下：在各种半重组无细胞和基于细胞的NOX 2试验中，GSK 2795039可抑制ROS的形成和酶底物NADPH和氧的利用。它以NADPH竞争性方式抑制NOX 2，并对其他NOX亚型、黄嘌呤氧化酶和内皮型一氧化氮合酶具有选择性。在小鼠全身给药后，GSK 2795039消除了爪炎症模型中活化的N 0X 2酶产生的ROS。此外，GSK 2795039在急性胰腺炎小鼠模型中显示出活性，降低了由雨蛙肽全身注射引发的血清淀粉酶水平。创新与结论：GSK 2795039是一种新型的NOX 2抑制剂，是第一种在体内表现出抑制NOX 2酶的小分子。抗氧化剂。氧化还原信号。23，358-374。
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. Antioxid. Redox Signal. 23, 358-374.