A prodrug form of VRT-043198
VX-765 is a newly developed, selective, small molecule caspase-1 inhibitor that can pass the blood-brain barrier and reduce inflammation in vitro and in vivo[1].
VX-765 potently and specifically inhibited human Casp1 (IC50 3.68?nM)[2]. Increases of autophagy-related proteins were detected in VX-765-pretreated human umbilical mesenchymal stem cells(HUMSCs), indicating the potential of VX-765 for up-regulating autophagy. Meanwhile, increased p-AMPK and decreased p-mTOR were detected in VX-765-pretreated HUMSCs. Furthermore, the anti-inflammatory and anti-apoptosis effect of VX-765 could be abolished by an autophagy inhibitor or AMPK inhibitor[3]
In vivo，VX-765 ameliorated renal dysfunction, tubular injury, and renal inflammation in mice with DN, but had no effect on blood glucose level or body weight, illustrating that VX-765 represents a novel and efficacious therapeutic treatment for DN without increasing the risk of hypoglycemia in diabetic patients[4]
参考文献:
[1]. Boxer MB, Quinn AM, et al. A highly potent and selective caspase 1 inhibitor that utilizes a key 3-cyanopropanoic acid moiety. ChemMedChem. 2010 May 3;5(5):730-8.
[2]. Flores J, No?l A, et al. Caspase-1 inhibition alleviates cognitive impairment and neuropathology in an Alzheimer's disease mouse model. Nat Commun. 2018 Sep 25;9(1):3916.
[3]. Sun Z, Gu L, et al. VX-765 enhances autophagy of human umbilical cord mesenchymal stem cells against stroke-induced apoptosis and inflammatory responses via AMPK/mTOR signaling pathway. CNS Neurosci Ther. 2020 Sep;26(9):952-961.
[4]. Wen S, Deng F, et al. VX-765 ameliorates renal injury and fibrosis in diabetes by regulating caspase-1-mediated pyroptosis and inflammation. J Diabetes Investig. 2022 Jan;13(1):22-33.
VX-765 是一种新开发的选择性小分子 caspase-1 抑制剂，可通过血脑屏障并在体外和体内减少炎症[1]。
VX-765 有效且特异性地抑制人 Casp1 (IC50 3.68 nM)[2]。在 VX-765 预处理的人脐带间充质干细胞 (HUMSCs) 中检测到自噬相关蛋白的增加，表明 VX-765 具有上调自噬的潜力。同时，在 VX-765 预处理的 HUMSC 中检测到增加的 p-AMPK 和减少的 p-mTOR。此外，VX-765 的抗炎和抗凋亡作用可被自噬抑制剂或 AMPK 抑制剂消除[3]
在体内，VX-765 改善了 DN 小鼠的肾功能障碍、肾小管损伤和肾脏炎症，但对血糖水平或体重没有影响，表明 VX-765 代表了一种新型有效的 DN 治疗方法不会增加糖尿病患者发生低血糖的风险[4]
| Cell experiment [1]: | |
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Cell lines |
human umbilical mesenchymal stem cells(HUMSCs) |
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Preparation Method |
MTT assay was used to test the toxicity of VX-765. Oxygen-glucose deprivation (OGD) was applied to mimic ischemic environment in vitro experiments, and The apoptosis of HUMSCs incubated with VX-765 was assessed 12 or 24 hours after OGD exposure. |
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Reaction Conditions |
10μM VX-765 for 12, 24h. |
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Applications |
Compared to OGD groups, TUNEL-positive cells, IL-1β, and IL-6 decreased while IL-10 increased in VX-765+OGD group. The result demonstrate the anti-apoptosis and anti- inflammatory role of VX-765 in HUMSCs. |
| Animal experiment [2]: | |
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Animal models |
CD1 (ICR) mice |
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Preparation Method |
CD1 (ICR) mice were injected intraperitoneally with 55?mg/kg streptozotocin(STZ). Mice with blood glucose level over 300?mg/dL were considered diabetic.Diabetic mice were administered with VX-765 for 8?weeks.The treatment with VX-765 was initiated 2?weeks after STZ injection |
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Dosage form |
100mg/kg VX-765, intraperitoneal(i.p.) injection |
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Applications |
Administration of VX-765 in diabetic mice effectively ameliorated renal function, compared with that of untreated diabetic mice.VX-765 treatment did not affect blood glucose level or body weight, illustrating that VX-765 ameliorated diabetic nephropathy independent of its metabolic effects. |
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参考文献: [1]. Sun Z, Gu L, et al. VX-765 enhances autophagy of human umbilical cord mesenchymal stem cells against stroke-induced apoptosis and inflammatory responses via AMPK/mTOR signaling pathway. CNS Neurosci Ther. 2020 Sep;26(9):952-961. [2]. Wen S, Deng F, et al. VX-765 ameliorates renal injury and fibrosis in diabetes by regulating caspase-1-mediated pyroptosis and inflammation. J Diabetes Investig. 2022 Jan;13(1):22-33. |
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