VAS 3947, a specific NADPH oxidase (NOX) inhibitor, exerts a potent antiplatelet effect. VAS3947 induces apoptosis independently of anti-NOX activity, via UPR activation, mainly due to aggregation and misfolding of proteins[1][2].
VAS3947 consistently inhibits NADPH oxidase activity in low micromolar concentrations, and interferes neither with ROS detection nor with XOD or eNOS activities. VAS3947 (30 µM) does not interfere with xanthine/XOD-derived L012 signals, suggesting this compound is free of antioxidant or scavenging effects relevant to ROS detection. In CaCo-2 cell homogenates, VAS3947 completely blocks NADPH-dependent ROS production with an IC50 of 12 µM[1].VAS3947 triggers cell proliferation arrest and death independently of anti-NOX activity. The IC50 values of the different cell lines ranges from 2.6 ± 0.6 µM for the most sensitive cell line MV-4-11 to 4.9 µM for THP-1, the least sensitive[2].VAS3947 decreases ROS levels. VAS3947 triggers endoplasmic reticulum (ER) stress and consequent unfolding protein response (UPR)[2].VAS3947 attenuates platelet activation and thrombus formation via a NOX-independent pathway downstream of PKC3].
NADPH 氧化酶抑制剂
[1]. Wind S, et al. Comparative pharmacology of chemically distinct NADPH oxidase inhibitors. Br J Pharmacol. 2010;161(4):885-898. [2]. El Dor M, et al. VAS3947 Induces UPR-Mediated Apoptosis through Cysteine Thiol Alkylation in AML Cell Lines. Int J Mol Sci. 2020;21(15):5470. Published 2020 Jul 31. [3]. Lu WJ, et al. VAS2870 and VAS3947 attenuate platelet activation and thrombus formation via a NOX-independent pathway downstream of PKC. Sci Rep. 2019;9(1):18852. Published 2019 Dec 11.