ChemicalBook Product Catalog Biochemical Engineering Inhibitors GSK484

GSK484

Product NameGSK484
CAS1652591-81-5
MFC27H32ClN5O3
MW510.04
EINECS
MOL File1652591-81-5.mol

Chemical Properties

storage temp.	2-8°C
solubility	DMSO:25.0(Max Conc. mg/mL);49.01(Max Conc. mM) Ethanol:25.0(Max Conc. mg/mL);49.01(Max Conc. mM) PBS buffer (pH 7.2):5.0(Max Conc. mg/mL);9.8(Max Conc. mM) DMF:30.0(Max Conc. mg/mL);58.82(Max Conc. mM)
form	powder
color	white to beige
Water Solubility	H2O: 2mg/mL, clear (warmed)
InChIKey	MULKOGJHUZTANI-JEGYXLSDNA-N
SMILES	C(C1CC1)N1C2=CC=CC=C2C=C1C1=NC2=CC(C(N3CC[C@@H](O)[C@@H](N)C3)=O)=CC(OC)=C2N1C.Cl \|&1:22,24,r\|

Safety Information

WGK Germany	WGK 3
HS Code	2933399990
Storage Class	11 - Combustible Solids

Usage And Synthesis

Description

GSK484 is a reversible inhibitor of PAD4 (IC₅₀ = 50 nM) that binds to the low-calcium form of the enzyme. It is selective for PAD4 over PAD1-3. GSK484 blocks the citrullination of PAD4 target proteins in human neutrophils and inhibits the formation of neutrophil extracellular traps in both mouse and human neutrophils. It exhibits favorable pharmacokinetic profiles in mouse and rat. See the Structural Genomics Consortium (SGC) website for more information.

Uses

GSK484 is a novel selective PAD4 inhibitor.

Biochem/physiol Actions

GSK484 is a potent selective reversible inhibitor of protein arginine deiminase PAD4, an enzyme believed to play a role in granulocyte and macrophage development leading to inflammation and immune response, and overexpressed in many tumors. GSK484 has IC50 values of 50 nM without calcium and 250 nM in the presence of 2 mM calcium. GSK484 showed minimal off-target activity tested against 50 other proteins with no activation across HDACs 1–11 even at 100 μM. GSK484 binds at a different site from the amidines, a conformation of the PAD4 active site where part of the site is reordered to form a β-hairpin.

in vivo

To address whether PAD4 inhibition can suppress cancer-associated kidney injury, MMTV-PyMT mice are treated with the PAD4 inhibitor GSK484 at 4 mg/kg daily for one week. This dose suppress the elevated number of neutrophils undergoing NETosis in peripheral blood in mice with cancer. In parallel, the total protein level in urine from MMTV-PyMT mice is significantly reduced compared with untreated tumor-bearing mice, further supporting an improved functional status of the kidneys after GSK484 treatment. Administration of GSK484 at a dose of 4 mg/kg daily during one week reverts signs of kidney dysfunction in tumor-bearing mice to the same extent as DNase I treatment, without any detectable signs of toxicity^[2].

References

[1] HUW D LEWIS. Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation[J]. Nature chemical biology, 2015, 11 3: 189-191. DOI: 10.1038/nchembio.1735
[2] MARINA LI. A Novel Peptidylarginine Deiminase 4 (PAD4) Inhibitor BMS-P5 Blocks Formation of Neutrophil Extracellular Traps and Delays Progression of Multiple Myeloma.[J]. Molecular Cancer Therapeutics, 2020, 19 7: 1530-1538. DOI: 10.1158/1535-7163.mct-19-1020
[3] YEBIN ZHOU. Evidence for a direct link between PAD4-mediated citrullination and the oxidative burst in human neutrophils.[J]. Scientific Reports, 2018: 15228. DOI: 10.1038/s41598-018-33385-z

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