GSK484 hydrochloride
目录号 : GC19184
GSK484是一种选择性PAD4抑制剂，已被用作抗缺血化合物，对PAD4具有抑制活性。
Cas No.:1652591-81-5
Sample solution is provided at 25 µL, 10mM.
GSK484 is a selective PAD4 inhibitor, has been used as an anti-ischemic compound and exerts inhibitory activity against PAD4. In the absence of calcium the IC50 value is 50 nM[1-2].
GSK484(25 nM; 1 h before irradiation) facilitated Triple-negative breast cancer (TNBC) cell apoptosis[3]. GSK484(100 nM; 15min) treatment promoted the radiosensitivity of CRC cells and induced cell death by promoting DNA double-strand breaks[4].
GSK484(4 mg/kg; i.p;40days) significantly inhibited tumor size, tumor weight and tumor volume in mice following irradiation in Nasopharyngeal carcinoma (NPC) mice model[5]. GSK484(4 mg/kg; i.p;3days) inhibits PAD4 to reduce distal lung injury by reducing neutrophil infiltration, neutrophil extracellular trap formation, apoptosis, and inflammatory cytokine secretion in mice ischemia reperfusion (IR) model[6].
References:
[1]. Perdomo J, Leung HHL, et,al. Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia. Nat Commun. 2019 Mar 21;10(1):1322.
[2]. Du M, Yang W, et,al. Inhibition of peptidyl arginine deiminase-4 protects against myocardial infarction induced cardiac dysfunction. Int Immunopharmacol. 2020 Jan;78:106055.
[3]. Wei L, Wang X, et,al. The PAD4 inhibitor GSK484 enhances the radiosensitivity of triple-negative breast cancer. Hum Exp Toxicol. 2021 Jul;40(7):1074-1083. Erratum in: Hum Exp Toxicol. 2021 Nov;40(11):2022.
[4]. Wang B, Su X, et,al. GSK484, an inhibitor of peptidyl arginine deiminase 4, increases the radiosensitivity of colorectal cancer and inhibits neutrophil extracellular traps. J Gene Med. 2023 Sep;25(9):e3530.
[5]. Chen H, Luo M, et,al. Inhibition of PAD4 enhances radiosensitivity and inhibits aggressive phenotypes of nasopharyngeal carcinoma cells. Cell Mol Biol Lett. 2021 Mar 16;26(1):9.
[6]. Du M, Yang L, et,al. Inhibition of Peptidyl Arginine Deiminase-4 Prevents Renal Ischemia-Reperfusion-Induced Remote Lung Injury. Mediators Inflamm. 2020 Dec 29;2020:1724206.
GSK484是一种选择性PAD4抑制剂，已被用作抗缺血化合物，对PAD4具有抑制活性。不含钙时IC50为50 nM[1-3]。
GSK484(25 nM; 1 h before irradiation)促进三阴性乳腺癌(TNBC)细胞凋亡[4]。GSK484(100 nM; 15min)通过促进DNA双链断裂，提高CRC细胞的放射敏感性，诱导细胞死亡[5]。
GSK484(4 mg/kg; i.p;40days)显著抑制鼻咽癌(NPC)小鼠辐照后的肿瘤大小、肿瘤重量和肿瘤体积[6]。在小鼠缺血再灌注(IR)模型中，GSK484(4 mg/kg; i.p;3days)通过减少中性粒细胞浸润、中性粒细胞胞外陷阱形成、细胞凋亡和炎性细胞因子分泌，抑制PAD4减轻远端肺损伤[7]。
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Fluorescence Polarization (FP) binding affinity studies [1]: |
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Preparation method |
PAD4 was serially diluted in the presence of 10 nM GSK484 in Assay Buffer (100 mM HEPES, pH 8, 50 mM NaCl, 5% glycerol, 1 mM CHAPS, 1 mM DTT) at varying concentrations of calcium (0 mM, 0.2 mM, 2 mM and 10 mM). Following incubation for 50 min, apparent Kd values for each calcium concentration were determined using a single site saturation curve. For IC50 determination, test compounds were serially diluted in DMSO (1% final assay concentration) and tested at the same range of calcium concentrations in the presence of PAD4 (at the calculated Kd for each calcium condition) and 10 nM GSK484 in the same assay buffer and volume. Reactions were incubated for 50 min, after which IC50 values were calculated. |
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Applications |
GSK484 demonstrated high affinity binding to the low-calcium form of PAD4 with IC50 50 nM(no Ca+). |
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Cell experiment [2]: |
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Cell lines |
MDA-MB-231 cells (Triple-negative breast cancer (TNBC)) |
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Preparation method |
GSK484 was dissolved in DMSO. The DMSO concentration of the solution used was consistently lower than 0.1%. Cells were grown to 70% -80% confluence on plates and cultivated with a low dose of GSK484 for 1 h before irradiation. |
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Reaction Conditions |
25 nM; 1 h before irradiation |
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Applications |
GSK484 facilitates cell apoptosis and promotes the radiosensitivity of MDA-MB-231 cells. |
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Animal experiment [2]: |
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Animal models |
Female BALB/c mice (6-week-old) |
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Preparation method |
MDA-MB-231 cells were injected subcutaneously into the 4th mammary fat pads of lactiferous ducts the in mice. Mice were randomly divided into four groups (Vehicle, 15 Gy alone, GSK484 4 mg/kg, and 15 Gy + GSK484 4 mg/kg). GSK484 was administered at a dose of 4 mg/kg ip in 2-hydroxypropyl-β-cyclodextrin at 1 hour before irradiation. The tumor areas were irradiated with 6 MV X-rays (15 Gy in one fraction) in 15 Gy alone and 15 Gy + GSK484 4 mg/kg groups. |
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Dosage form |
4 mg/kg; i.p.; 1 hour before irradiation |
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Applications |
Treatment with GSK484 and ischemia reperfusion (IR), the tumor volume and body weight of mice decreased significantly. |
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References: [1]. Lewis HD, Liddle J, et,al. Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation. Nat Chem Biol. 2015 Mar;11(3):189-91. doi: 10.1038/nchembio.1735. Epub 2015 Jan 26. PMID: 25622091; PMCID: PMC4397581. |
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| Cas No. | 1652591-81-5 | SDF | |
| Canonical SMILES | O=C(N1C[C@H](N)[C@H](O)CC1)C2=CC(OC)=C3C(N=C(C(N4CC5CC5)=CC6=C4C=CC=C6)N3C)=C2.[H]Cl | ||
| 分子式 | C27H32ClN5O3 | 分子量 | 510.03 |
| 溶解度 | DMSO : 125 mg/mL (245.08 mM; Need ultrasonic); H20 : 50 mg/mL (98.03 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.9607 mL | 9.8033 mL | 19.6067 mL |
| 5 mM | 0.3921 mL | 1.9607 mL | 3.9213 mL |
| 10 mM | 0.1961 mL | 0.9803 mL | 1.9607 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet