Dynasore

Dynasore, as a GTPase inhibitor, can rapidly and reversibly inhibit dynamin activity, which prevents endocytosis^[1].

Dynasore inhibits dynamin GTPase activity and transferrin uptake with IC50 of approximately 15 μM^[2]. In vitro, treatment with 80 μM dynasore commonly block dynamin 1 and 2, dynasore also has a potent inhibition on ferroptosis at a range of lower concentrations. Dynasore also potently blocked H2O2-induced cell death at 100 nM^[3]. In vitro experiment it demonstrated that treatment with 100 μM dynasore impairs VEGF-induced calcium release^[4]. At the ocular surface of ex vivo mouse eyes, 40 uM dynasore blocked stress-stimulated dye uptake. Dynasore is obviously protective of cells and their surface glycocalyx, preventing damage due to oxidative stress, and thus precluding dye entry^[5]. In vitro test it exhibited that treatment with 100 μM dynasore rapidly increased the spontaneous EPSC (sEPSC) frequency which was followed by inhibition of both solitary tract-evoked EPSCs (ST-EPSC) as well as asynchronous EPSCs^[6]. In peritoneal macrophages and LLC-MK2 cells, treatment with 100 μM dynasore drastically diminished the parasite internalization^[7].

In vivo efficacy test it shown that dynasore (10 mg/kg, intraperitoneally) inhibits OS tumorigenesis without inducing nephrotoxicity and hepatotoxicity^[8]. In vivo, the ocular mouse Sereny model was administrated 30 mg/kg intraperitoneally did not reduce ocular inflammation, it did provide significant protection against weight loss^[9].

References:

^[1] Preta G, et al. Dynasore - not just a dynamin inhibitor. Cell Commun Signal. 2015 Apr 10;13:24.

^[2] Lee S, et al. Synthesis of potent chemical inhibitors of dynamin GTPase. Bioorg Med Chem Lett. 2010 Aug 15;20(16):4858-64.

^[3] Clemente LP, et al. Dynasore Blocks Ferroptosis through Combined Modulation of Iron Uptake and Inhibition of Mitochondrial Respiration. Cells. 2020 Oct 9;9(10):2259.

^[4] Webster A, et al. Dynasore protects the ocular surface against damaging oxidative stress. PLoS One. 2018 Oct 10;13(10):e0204288.

^[5] Hofmann ME, et al. Dynasore blocks evoked release while augmenting spontaneous synaptic transmission from primary visceral afferents. PLoS One. 2017 Mar 30;12(3):e0174915.

^[6] Lum M, et al. Impact of dynasore an inhibitor of dynamin II on Shigella flexneri infection. PLoS One. 2013 Dec 19;8(12):e84975.

^[7] Zhong B, et al. Dynasore suppresses cell proliferation, migration, and invasion and enhances the antitumor capacity of cisplatin via STAT3 pathway in osteosarcoma. Cell Death Dis. 2019 Sep 18;10(10):687.

^[8] Basagiannis D, et al. Dynasore impairs VEGFR2 signalling in an endocytosis-independent manner. Sci Rep. 2017 Mar 22;7:45035.

^[9] Barrias ES, et al. Dynasore, a dynamin inhibitor, inhibits Trypanosoma cruzi entry into peritoneal macrophages. PLoS One. 2010 Jan 20;5(1):e7764.

Dynasore 作为 GTPase 抑制剂，可以快速、可逆地抑制发动蛋白活性，从而阻止内吞作用^[1]。

Dynasore 抑制发动蛋白 GTPase 活性和转铁蛋白摄取，IC50 约为 15 μM^[2]。在体外，用 80 μM dynasore 处理通常会阻断发动蛋白 1 和 2，在较低浓度范围内，dynasore 也对铁死亡具有有效的抑制作用。 Dynasore 还在 100 nM^[3] 时有效地阻断 H2O2 诱导的细胞死亡。体外实验表明，100 μM dynasore 处理会损害 VEGF 诱导的钙释放^[4]。在离体小鼠眼睛的眼表面，40 uM dynasore 阻断了应激刺激的染料摄取。 Dynasore 明显保护细胞及其表面糖萼，防止氧化应激引起的损伤，从而阻止染料进入^[5]。体外试验表明，用 100 μM dynasore 处理可迅速增加自发性 EPSC (sEPSC) 频率，随后抑制孤立束诱发 EPSC (ST-EPSC) 以及异步 EPSC^{[6]。在腹膜巨噬细胞和 LLC-MK2 细胞中，用 100 μM dynasore 处理可显着减少寄生虫内化[7]。}

体内药效试验表明，dynasore（10 mg/kg，腹膜内注射）可抑制 OS 肿瘤发生，而不会引起肾毒性和肝毒性^[8]。在体内，眼部小鼠 Sereny 模型腹膜内给药 30 mg/kg 并没有减少眼部炎症，它确实提供了显着的体重减轻保护作用^[9]。