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Purity: ≥98%
GSK484 is a novel and potent inhibitor of peptidylarginine deiminase 4 (PAD4). GSK484 demonstrates high binding affinity to PAD4 with an IC50 of 50 nM in the absence of Calcium. In the presence of 2 mM Calcium, notably lower potency (250 nM) is observed. PAD4 has been strongly implicated in the pathogenesis of autoimmune, cardiovascular and oncological diseases through clinical genetics and gene disruption in mice. New selective PAD4 inhibitors binding a calcium-deficient form of the PAD4 enzyme have validated the critical enzymatic role of human and mouse PAD4 in both histone citrullination and neutrophil extracellular trap formation for, to our knowledge, the first time. The therapeutic potential of PAD4 inhibitors can now be explored.
| ln Vitro |
In the absence of calcium (0 mM) and calcium (2 mM), respectively, GSK484 hydrochloride binds to the low calcium version of PAD4 with a high affinity, IC50 values of 50 nM and 250 nM. Using an NH3 release test, GSK484 hydrochloride also showed concentration-dependent inhibition of PAD4 acidification on the benzoyl arginic acid ethyl ester (BAEE) substrate (at 0.2 mM calcium) [1].
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| ln Vivo |
In order to investigate if PAD4 inhibition can mitigate kidney damage associated with cancer, MMTV-PyMT mice were given 4 mg/kg of the PAD4 dye GSK484 hydrochloride every day for a week. Concurrently, total protein levels in MMTV-PyMT mice were considerably lower than in tumor-bearing mice treated by default, which provided additional evidence for the improved kidney functional status following GSK484 hydrochloride administration. Renal impairment was eventually recovered in tumor-bearing animals to the same degree as that observed with DNase I treatment after a week of daily application of GSK484 hydrochloride at a dose of 4 mg/kg, all without observable toxicity [2].
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| References |
[1]. Lewis HD, et al. Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation. Nat Chem Biol. 2015 Mar;11(3):189-91.
[2]. Cedervall J, et al. Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer-associated kidney injury in mice. Oncoimmunology. 2017 Apr 20;6(8):e1320009 |
| Molecular Formula |
C27H32CLN5O3
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|---|---|
| Molecular Weight |
510.0277
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| CAS # |
1652591-81-5
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| Related CAS # |
1652629-23-6;1652591-81-5 (HCl);
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| SMILES |
O=C(N1C[C@H](N)[C@H](O)CC1)C2=CC(OC)=C3N(C)C(C(N4CC5CC5)=CC6=C4C=CC=C6)=NC3=C2.[H]Cl
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| InChi Key |
MULKOGJHUZTANI-ADMBKAPUSA-N
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| InChi Code |
InChI=1S/C27H31N5O3.ClH/c1-30-25-20(11-18(13-24(25)35-2)27(34)31-10-9-23(33)19(28)15-31)29-26(30)22-12-17-5-3-4-6-21(17)32(22)14-16-7-8-16;/h3-6,11-13,16,19,23,33H,7-10,14-15,28H2,1-2H3;1H/t19-,23+;/m0./s1
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| Chemical Name |
((3S,4R)-3-amino-4-hydroxypiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone hydrochloride
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| Synonyms |
GSK484; GSK-484; GSK 484.
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~125 mg/mL (~245.08 mM)
H2O : ~50 mg/mL (~98.03 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.08 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.08 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.08 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 50 mg/mL (98.03 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. Solubility in Formulation 5: 100 mg/mL (196.07 mM) in Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. |
| Preparing Stock Solutions | 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 |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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