GSK484 HCl
[CAS# 1652591-81-5]

Identification

• Classification: Biochemical >> Inhibitor >> Epigenetics >> Epigenetic reader domain inhibitor
• Name: GSK484 HCl
• Synonyms: ((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
• Molecular Formula: C₂₇H₃₂ClN₅O₃
• Molecular Weight: 510.03
• CAS Registry Number: 1652591-81-5
• SMILES: CN1C2=C(C=C(C=C2OC)C(=O)N3CC[C@H]([C@H](C3)N)O)N=C1C4=CC5=CC=CC=C5N4CC6CC6.Cl

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H315-H319-H335
• Precautionary Statements: P261-P305+P351+P338

Discovory and Applicatios

GSK484 hydrochloride is a chemical compound identified as a potent and selective inhibitor of peptidylarginine deiminase 4 (PAD4), an enzyme implicated in various inflammatory and autoimmune diseases. The compound is a benzoimidazole derivative with a molecular formula of C₂₇H₃₁ClN₅O₃·HCl and a molecular weight of 510.03 g/mol. It is typically supplied as a hydrochloride salt to enhance its stability and solubility in aqueous solutions.

The discovery of GSK484 hydrochloride emerged from efforts to identify selective inhibitors of PAD4, which plays a crucial role in the post-translational modification of proteins through citrullination. This modification is associated with the pathogenesis of several diseases, including rheumatoid arthritis, where PAD4-mediated citrullination contributes to the formation of autoantigens and the perpetuation of inflammation. By inhibiting PAD4 activity, GSK484 hydrochloride aims to mitigate these pathological processes.

In biochemical assays, GSK484 hydrochloride has demonstrated an inhibitory concentration (IC₅₀) of approximately 50 nM in the absence of calcium ions, indicating a high affinity for the enzyme. Its selectivity is notable, as it exhibits minimal off-target activity against other PAD isoforms (PAD1, PAD2, and PAD3), even at concentrations up to 100 μM. This selectivity is attributed to its binding to a distinct site on the PAD4 enzyme, which undergoes conformational changes in the low-calcium state, facilitating the interaction with GSK484 hydrochloride.

The compound has been utilized in various preclinical studies to elucidate the role of PAD4 in disease models. For instance, in models of rheumatoid arthritis, GSK484 hydrochloride administration has been shown to reduce the formation of neutrophil extracellular traps (NETs), structures that contribute to tissue damage and inflammation. Additionally, the compound has been employed to investigate PAD4's involvement in other conditions such as acute kidney injury, lung inflammation, heart muscle damage following myocardial infarction, osteoporosis, diabetes, and certain cancers.

GSK484 hydrochloride is typically administered in vitro in cell-based assays using concentrations ranging from 10 to 100 μM, depending on the specific experimental setup and the cell type under investigation. It is soluble in dimethyl sulfoxide (DMSO) and is often used in combination with other reagents to assess its effects on PAD4 activity and downstream inflammatory pathways.

In summary, GSK484 hydrochloride is a selective and potent inhibitor of PAD4, with applications in research aimed at understanding the enzyme's role in various inflammatory and autoimmune diseases. Its development has provided valuable insights into PAD4's function and has potential therapeutic implications for conditions characterized by aberrant citrullination and inflammation.

References

2015. Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation. Nature Chemical Biology, 11(3).
DOI: 10.1038/nchembio.1735

2020. The PAD4 inhibitor GSK484 enhances the radiosensitivity of triple-negative breast cancer. Human & Experimental Toxicology, 40(7).
DOI: 10.1177/0960327120979028

2023. GSK484, an inhibitor of peptidyl arginine deiminase 4, increases the radiosensitivity of colorectal cancer and inhibits neutrophil extracellular traps. The Journal of Gene Medicine, 25(8).
DOI: 10.1002/jgm.3530