GSK-484 - CAS 1652591-81-5
Catalog number: 1652591-81-5
Category: Inhibitor
Please be kindly noted products are not for therapeutic use. We do not sell to patients.
Molecular Formula:
C27H32ClN5O3
Molecular Weight:
510.04
COA:
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Targets:
Others
Description:
GSK-484, a benzoimidazole derivative, has been found to be an effective reversible PAD-4 inhibitor that could be significant in some inflammation and immune response studies and probably have potential activities in anticancer studies. IC50: 50nM (without calcium), 250 nM (2 mM calcium exists).
Purity:
98%
Appearance:
Powder
Synonyms:
GSK484; GSK 484; GSK-484; ((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
Storage:
Store in a cool and dry place and at 0 - 4 °C for short term (days to weeks) or -20 °C for long term (months to years).
MSDS:
Inquire
Quality Standard:
In-house standard
Quantity:
Milligram-Grams
InChIKey:
MULKOGJHUZTANI-ADMBKAPUSA-N
InChI:
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
Canonical SMILES:
CN1C2=C(C=C(C=C2OC)C(=O)N3CCC(C(C3)N)O)N=C1C4=CC5=CC=CC=C5N4CC6CC6.Cl
1.Protein Deiminase 4 and CR3 Regulate
Clark HL;Abbondante S;Minns MS;Greenberg EN;Sun Y;Pearlman E Front Immunol. 2018 May 29;9:1182. doi: 10.3389/fimmu.2018.01182. eCollection 2018.
Neutrophil extracellular trap (NET) formation requires chromatin decondensation before nuclear swelling and eventual extracellular release of DNA, which occurs together with nuclear and cytoplasmic antimicrobial proteins. A key mediator of chromatin decondensation is protein deiminase 4 (PAD4), which catalyzes histone citrullination. In the current study, we examined the role of PAD4 and NETosis following activation of neutrophils by ;A. fumigatus; hyphal extract or cell wall β-glucan (curdlan) and found that both induced NET release by human and murine neutrophils. Also, using blocking antibodies to CR3 and Dectin-1 together with CR3-deficient CD18;-/-; and Dectin-1;-/-; murine neutrophils, we found that the β-glucan receptor CR3, but not Dectin-1, was required for NET formation. NETosis was also dependent on NADPH oxidase production of reactive oxygen species (ROS). Using an antibody to citrullinated histone 3 (H3Cit) as an indicator of PAD4 activity, we show that β-glucan stimulated NETosis occurs in neutrophils from C57BL/6, but not PAD4;-/-; mice. Similarly, a small molecule PAD4 inhibitor (GSK484) blocked NET formation by human neutrophils. Despite these observations, the ability of PAD4;-/-; neutrophils to release calprotectin and kill ;A.
2.Trophozoites Induce a Rapid Non-classical NETosis Mechanism Independent of NOX2-Derived Reactive Oxygen Species and PAD4 Activity.
Díaz-Godínez C;Fonseca Z;Néquiz M;Laclette JP;Rosales C;Carrero JC Front Cell Infect Microbiol. 2018 Jun 5;8:184. doi: 10.3389/fcimb.2018.00184. eCollection 2018.
Neutrophil extracellular traps (NETs) are DNA fibers decorated with histones and antimicrobial proteins from cytoplasmic granules released into the extracellular space in a process denominated NETosis. The molecular pathways involved in NETosis have not been completely understood. Classical NETosis mechanisms involve the neutrophil elastase (NE) translocation to nucleus due to the generation of reactive oxygen species (ROS) by NADPH oxidase (NOX2) or the peptidyl arginine deiminase 4 (PAD4) activation in response to an increase in extracellular calcium influx; both mechanisms result in DNA decondensation. Previously, we reported that trophozoites and lipopeptidophosphoglycan from ;Entamoeba histolytica; trigger NET release in human neutrophils. Here, we demonstrated in a quantitative manner that NETs were rapidly form upon treatment with amoebic trophozoites and involved both nuclear and mitochondrial DNA (mtDNA). NETs formation depended on amoeba viability as heat-inactivated or paraformaldehyde-fixed amoebas were not able to induce NETs. Interestingly, ROS were not detected in neutrophils during their interaction with amoebas, which could explain why NOX2 inhibition using apocynin did not affect this NETosis.
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