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CAS No.: 1346547-00-9

GSK583 Catalog No. CSN17724

GSK583 is a selective inhibitor of RIP2 Kinase and IC50 value is 5 nM.

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技术信息

生物活性

描述RIP2 kinase is a central component of the innate immune system and enables downstream signaling following activation of the pattern recognition receptors NOD1 and NOD2 (nucleotide-binding oligomerization domain-containing proteins 1 and 2), leading to the production of inflammatory cytokines. GSK583 is a highly effective and selective RIP2 kinase inhibitor with IC₅₀ value of 5 nM. GSK583 exhibited excellent selectivity in a panel of 300 kinases at 1 μM compound concentration. In this panel, only RIP2 was inhibited >50% by GSK583 and only two additional kinases were inhibited by approximately 30% (BRK, Aurora A). Following treatment with GSK583 at 1 μM, complete inhibition was observed upon activation of both NOD1 and NOD2 receptors, which signal in a RIP2-dependent manner. The pharmacokinetic parameters of GSK583 are consistent across rodent species exemplifying low clearance, moderate volumes of distribution, and moderate oral bioavailability. A combination of models which measured local and systemic inflammatory responses to intraperitoneal injection of L18-MDP in mice and intravenous injection of L18-MDP in rats with oral doses of GSK583 of 0.1, 1, and 10 mg/kg was employed to demonstrate the utility of GSK583. It inhibited serum KC (the rodent orthologue of IL-8) levels in rats in a dose-dependent manner, with an IC₅₀ derived from rat blood concentrations of 50 nM (or 20 ng/mL). Similarly, it inhibited serum KC levels (data not shown) and recruitment of neutrophils into the peritoneal cavity in mice in a dose-dependent manner, with an IC₅₀ of 37 nM (15 ng/mL) derived from mouse blood concentrations. As expected, a single oral dose of 10 mg/kg of GSK583 also inhibited the increase in serum levels of KC following administration of the NOD1 ligand, FK156 in mice^[2].
作用机制GSK583 binds to the human RIP2 catalytic domain (res 1–310)^[2].
参考文献

[1] Haile PA, Votta BJ, et al. The Identification and Pharmacological Characterization of 6-(tert-Butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583), a Highly Potent and Selective Inhibitor of RIP2 Kinase. J Med Chem, 2016 May 26, 59(10):4867-80
[2] Haile PA, Votta BJ, Marquis RW, et al. The Identification and Pharmacological Characterization of 6-(tert-Butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583), a Highly Potent and Selective Inhibitor of RIP2 Kinase. J Med Chem. 2016;59(10):4867‐4880

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 2.5097 mL
- 12.5485 mL
- 25.0970 mL
- 5 mM
- 0.5019 mL
- 2.5097 mL
- 5.0194 mL
- 10 mM
- 0.2510 mL
- 1.2549 mL
- 2.5097 mL

技术信息

CAS号

1346547-00-9

储存条件

粉末: Keep in dark place,Inert atmosphere,2-8°C

液体: -20°C:3-6 月 -80°C:12月

分子式

C20H19FN4O2S

运输

蓝冰

分子量

398.45

别名

溶解度

DMSO	79.0 mg/mL (198.3 mM)
Water	Insoluble
Ethanol	28.0 mg/mL (70.3 mM)

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