SU5416

SU5416 is a potent small molecule vascular endothelial growth factor receptor (VEGFR) inhibitor. SU5416 is a 3-substituted indolin-2-one compound with relatively high specificity for VEGFR-2 and VEGFR-1, used extensively in animal models of PH, primarily due to effects on pulmonary vascular endothelial cell apoptosis and proliferation.[1] SU416 has been developed for the treatment of solid human tumors as well. ^[3]

In vitro study was performed to examine the inhibitory effect of SU5416 on KDR phosphorylation. Which indicated that pretreatment of BCECs with SU5416 resulted in a dose-dependent inhibition of KDR phosphorylation with an IC50 of 0.29 ± 0.071 μM (n=6) SU5416 almost completely inhibited KDR phosphorylation at the concentration of 3 μM. Few BCECs were stained with trypan blue after the treatment of SU5416, at least up to the concentration of 3 μM for 24 h. This suggested that the inhibitory effect of SU5416 on KDR phosphorylation was not due to the cell toxicity.^[2]

In vivo study demonstrated that SU5416 could significantly reverse LPS-induced ALI in mice, and exert better protective effect in TLR4 knockout mice. SU5416 could also act as a protective agent against LPS-induced ALI in mice. Moreover, SU5416 dramatically restored the reduction of CD31 expression mediated by LPS, suggesting SU5416 could rescue LPS-induced dysfunction of pulmonary endothelial barrier. In addition, both p-VEGFR2 and VEGFR2 expressions were inhibited by SU5416 in WT and TLR4?/- mice. SU5416 could attenuate LPS-induced ALI through modulating the VEGF/VEGFR and NF-κB pathways, which suggested SU5416 might be used for the treatment of patients with inflammation-mediated ALI.^[3]

References:
[1]. Peloquin GL, et al. SU5416 does not attenuate early RV angiogenesis in the murine chronic hypoxia PH model. Respir Res. 2019 Jun 17;20(1):123.
[2] Takeda A, et al. Suppression of experimental choroidal neovascularization utilizing KDR selective receptor tyrosine kinase inhibitor. Graefes Arch Clin Exp Ophthalmol. 2003 Sep;241(9):765-72.
[3]. Huang X, et al. SU5416 attenuated lipopolysaccharide-induced acute lung injury in mice by modulating properties of vascular endothelial cells. Drug Des Devel Ther. 2019 May 23;13:1763-1772.

SU5416 是一种有效的小分子血管内皮生长因子受体 (VEGFR) 抑制剂。 SU5416 是一种 3-取代的二氢吲哚-2-酮化合物，对 VEGFR-2 和 VEGFR-1 具有相对较高的特异性，广泛用于 PH 动物模型，主要是由于对肺血管内皮细胞凋亡和增殖的影响。 [1] SU416 也已开发用于治疗实体人类肿瘤。 ^[3]

进行了体外研究以检查 SU5416 对 KDR 磷酸化的抑制作用。这表明用 SU5416 预处理 BCECs 导致 KDR 磷酸化的剂量依赖性抑制，IC50 为 0.29 ± 0.071 μM (n=6) SU5416 在 3 μM 的浓度下几乎完全抑制 KDR 磷酸化。在 SU5416 处理后，很少有 BCEC 被台盼蓝染色，至少达到 3 μM 的浓度 24 小时。这表明SU5416对KDR磷酸化的抑制作用不是由于细胞毒性。^[2]

体内研究表明，SU5416 可显着逆转 LPS 诱导的小鼠 ALI，并对 TLR4 基因敲除小鼠发挥更好的保护作用。 SU5416 还可以作为 LPS 诱导的小鼠 ALI 的保护剂。此外，SU5416 显着恢复了 LPS 介导的 CD31 表达降低，表明 SU5416 可以挽救 LPS 诱导的肺内皮屏障功能障碍。此外，在 WT 和 TLR4-/- 小鼠中，p-VEGFR2 和 VEGFR2 表达均被 SU5416 抑制。 SU5416可通过调节VEGF/VEGFR和NF-κB通路减轻LPS诱导的ALI，提示SU5416可用于治疗炎症介导的ALI。^[3]