Cl-Amidine

Inhibits protein-arginine deiminase (PAD)

Cl-Amidine

Inhibits protein-arginine deiminase (PAD)

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Inhibits protein-arginine deiminase (PAD)
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Overview

Cl-Amidine is a protein-arginine deiminase (PAD) inhibitor that irreversibly inactivates four subtypes of PAD (kinact/Ki = 37,000/PAD1, 1,200/PAD2, 2,000/PAD3, and 13,000/PAD4 M-1min-1; Knuckley et al.; Luo et al.; Slack et al.) by modifying the enzyme’s active site. This product is supplied as the hydrochloride salt of the molecule.

IMMUNOLOGY
· Inhibits neutrophil extracellular traps formation in neutrophils (Knight et al.).
· Prevents hypercitrullination of histone H3 in neutrophils (Knight et al.).

CANCER RESEARCH
· Exhibits cytotoxic effects toward human leukemia (IC50 = 0.25 μM), breast (IC50 = 0.05 μM), and colon (IC50 = 1 μM) cancer cell lines (Slack et al.).
Alternative Names
Not applicable
Cell Type
Cancer Cells and Cell Lines, Granulocytes and Subsets
Area of Interest
Cancer, Immunology
CAS Number
1373232-26-8
Chemical Formula
C14H19ClN4O2 • HCl
Molecular Weight
347.2 g/mol
Purity
≥ 95%

Protocols and Documentation

Find supporting information and directions for use in the Product Information Sheet or explore additional protocols below.

Document Type
Product Name
Catalog #
Lot #
Language
Catalog #
100-0519
Lot #
All
Language
English
Product Name
Cl-Amidine
Catalog #
100-0518
Lot #
All
Language
English
Document Type
Safety Data Sheet
Catalog #
100-0519
Lot #
All
Language
English
Document Type
Safety Data Sheet
Product Name
Cl-Amidine
Catalog #
100-0518
Lot #
All
Language
English

Resources and Publications

Publications (5)

Peptidylarginine deiminase inhibition disrupts NET formation and protects against kidney, skin and vascular disease in lupus-prone MRL/lpr mice. J. S. Knight et al. Annals of the rheumatic diseases 2015 dec

Abstract

OBJECTIVES An imbalance between neutrophil extracellular trap (NET) formation and degradation has been described in systemic lupus erythematosus (SLE), potentially contributing to autoantigen externalisation, type I interferon synthesis and endothelial damage. We have demonstrated that peptidylarginine deiminase (PAD) inhibition reduces NET formation and protects against lupus-related vascular damage in the New Zealand Mixed model of lupus. However, another strategy for inhibiting NETs--knockout of NOX2--accelerates lupus in a different murine model, MRL/lpr. Here, we test the effects of PAD inhibition on MRL/lpr mice in order to clarify whether some NET inhibitory pathways may be consistently therapeutic across models of SLE. METHODS NET formation and autoantibodies to NETs were characterised in lupus-prone MRL/lpr mice. MRL/lpr mice were also treated with two different PAD inhibitors, Cl-amidine and the newly described BB-Cl-amidine. NET formation, endothelial function, interferon signature, nephritis and skin disease were examined in treated mice. RESULTS Neutrophils from MRL/lpr mice demonstrate accelerated NET formation compared with controls. MRL/lpr mice also form autoantibodies to NETs and have evidence of endothelial dysfunction. PAD inhibition markedly improves endothelial function, while downregulating the expression of type I interferon-regulated genes. PAD inhibition also reduces proteinuria and immune complex deposition in the kidneys, while protecting against skin disease. CONCLUSIONS PAD inhibition reduces NET formation, while protecting against lupus-related damage to the vasculature, kidneys and skin in various lupus models. The strategy by which NETs are inhibited will have to be carefully considered if human studies are to be undertaken.
Peptidylarginine deiminase inhibition is immunomodulatory and vasculoprotective in murine lupus. J. S. Knight et al. The Journal of clinical investigation 2013 jul

Abstract

Recent evidence suggests that enhanced neutrophil extracellular trap (NET) formation activates plasmacytoid dendritic cells and serves as a source of autoantigens in SLE. We propose that aberrant NET formation is also linked to organ damage and to the premature vascular disease characteristic of human SLE. Here, we demonstrate enhanced NET formation in the New Zealand mixed 2328 (NZM) model of murine lupus. NZM mice also developed autoantibodies to NETs as well as the ortholog of human cathelicidin/LL37 (CRAMP), a molecule externalized in the NETs. NZM mice were treated with Cl-amidine, an inhibitor of peptidylarginine deiminases (PAD), to block NET formation and were evaluated for lupus-like disease activity, endothelial function, and prothrombotic phenotype. Cl-amidine treatment inhibited NZM NET formation in vivo and significantly altered circulating autoantibody profiles and complement levels while reducing glomerular IgG deposition. Further, Cl-amidine increased the differentiation capacity of bone marrow endothelial progenitor cells, improved endothelium-dependent vasorelaxation, and markedly delayed time to arterial thrombosis induced by photochemical injury. Overall, these findings suggest that PAD inhibition can modulate phenotypes crucial for lupus pathogenesis and disease activity and may represent an important strategy for mitigating cardiovascular risk in lupus patients.
Protein arginine deiminase 4: a target for an epigenetic cancer therapy. J. L. Slack et al. Cellular and molecular life sciences : CMLS 2011 feb

Abstract

The recent approvals of anticancer therapeutic agents targeting the histone deacetylases and DNA methyltransferases have highlighted the important role that epigenetics plays in human diseases, and suggested that the factors controlling gene expression are novel drug targets. Protein arginine deiminase 4 (PAD4) is one such target because its effects on gene expression parallel those observed for the histone deacetylases. We demonstrated that F- and Cl-amidine, two potent PAD4 inhibitors, display micromolar cytotoxic effects towards several cancerous cell lines (HL-60, MCF7 and HT-29); no effect was observed in noncancerous lines (NIH 3T3 and HL-60 granulocytes). These compounds also induced the differentiation of HL-60 and HT29 cells. Finally, these compounds synergistically potentiated the cell killing effects of doxorubicin. Taken together, these findings suggest PAD4 inhibition as a novel epigenetic approach for the treatment of cancer, and suggest that F- and Cl-amidine are candidate therapeutic agents for this disease.