1. Epigenetics
  2. Protein Arginine Deiminase
  3. GSK484 hydrochloride

GSK484 hydrochloride (Synonyms: GTPL8577; AOB6992)

Cat. No.: HY-100514 Purity: 98.00%
Handling Instructions

GSK484 hydrochloride is a peptidylarginine deiminase 4 (PAD4) inhibitor. GSK484 hydrochloride demonstrates high affinity binding to PAD4 with IC50s of 50 nM in the absence of Calcium. In the presence of 2 mM Calcium, notably lower potency (250 nM) is observed.

For research use only. We do not sell to patients.

GSK484 hydrochloride Chemical Structure

GSK484 hydrochloride Chemical Structure

CAS No. : 1652591-81-5

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10 mM * 1 mL in DMSO USD 213 In-stock
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50 mg USD 990 In-stock
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100 mg USD 1700 In-stock
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Based on 1 publication(s) in Google Scholar

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Description

GSK484 hydrochloride is a peptidylarginine deiminase 4 (PAD4) inhibitor. GSK484 hydrochloride demonstrates high affinity binding to PAD4 with IC50s of 50 nM in the absence of Calcium. In the presence of 2 mM Calcium, notably lower potency (250 nM) is observed.

IC50 & Target

IC50: 50 nM (PAD4, in the absence of Calcium), 250 nM (PAD4, in the presence of 2 mM Calcium)[1]

In Vitro

GSK484 demonstrates high affinity binding to the low-calcium form of PAD4 with IC50s of 50 nM and 250 nM in the absence of Calcium (0 mM) and Calcium (2 mM), respectively. GSK484 also inhibits PAD4 citrullination (at 0.2 mM Calcium) of benzoyl-arginine ethyl ester (BAEE) substrate in a concentration-dependent manner, as detected using an NH3 release assay[1].

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].

Molecular Weight

510.03

Formula

C₂₇H₃₂ClN₅O₃

CAS No.

1652591-81-5

SMILES

O=C(N1C[[email protected]](N)[[email protected]](O)CC1)C2=CC(OC)=C3C(N=C(C(N4CC5CC5)=CC6=C4C=CC=C6)N3C)=C2.[H]Cl

Shipping

Room temperature in continental US; may vary elsewhere

Storage

4°C, stored under nitrogen

*In solvent : -80°C, 6 months; -20°C, 1 month (stored under nitrogen)

Solvent & Solubility
In Vitro: 

DMSO : 62.5 mg/mL (122.54 mM; Need ultrasonic)

Preparing
Stock Solutions
Concentration Solvent Mass 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
*Please refer to the solubility information to select the appropriate solvent.
In Vivo:
  • 1.

    Add each solvent one by one:  10% DMSO    40% PEG300    5% Tween-80    45% saline

    Solubility: ≥ 2.08 mg/mL (4.08 mM); Clear solution

  • 2.

    Add each solvent one by one:  10% DMSO    90% (20% SBE-β-CD in saline)

    Solubility: ≥ 2.08 mg/mL (4.08 mM); Clear solution

  • 3.

    Add each solvent one by one:  10% DMSO    90% corn oil

    Solubility: 2.08 mg/mL (4.08 mM); Clear solution; Need warming

*All of the co-solvents are provided by MCE.
References
Kinase Assay
[1]

PAD4 is serially diluted in the presence of 10 nM GSK215 in assay buffer (100 mM HEPES, pH 8, 50 mM NaCl, 5% glycerol, 1 mM CHAPS, 1 mM DTT) at varying concentrations of calcium (0, 0.2, 2 and 10 mM). Following incubation for 50 min, apparent Kds for each calcium concentration are determined using a single site saturation curve. For IC50 determination, test compounds (e.g., GSK484) are serially diluted in DMSO (1% final assay concentration) and tested at the same range of calcium concentrations in the presence of PAD4 (at the calculated Kd for each calcium condition) and 10 nM GSK215 in the same assay buffer and volume. Reactions are incubated for 50 min after which IC50 values are calculated using a four-parameter logistic equation[1].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Assay
[1]

HEK293 cells stably expressing N-terminal FLAG-tagged PAD1, PAD2, PAD3 or PAD4 are engineered by retroviral transduction. Cells are grown in 15 cm diameter plates to subconfluency in DMEM supplemented with 10% Foetal Bovine Serum, harvested by centrifugation and washed once in PBS/2 mM EGTA. Cells are lysed in 50 mM Tris-Cl, pH 7.4, 1.5 mM MgCl2, 5% glycerol, 150 mM NaCl, 25 mM NaF, 1 mM Na3VO4, 0.4% NP40, 1 mM DTT with protease inhibitors. Lysates are pre-incubated for 20 min at 4°C with DMSO alone (2%), 100 µM of GSK199, GSK484, GSK106 or 200 µM Cl-amidine. Citrullination reactions are performed for 30 min at 37°C in the presence of 2 mM calcium. Extracts are loaded on to gels, proteins separated by SDS-PAGE and transferred to PVDF membranes. Citrullinated proteins are then chemically modified and detected using anti-modified citrulline antibody. FLAG-PAD constructs are detected using anti-FLAG antibody[1].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Administration
[2]

Mice[2]
The study includes two transgenic mouse models, the MMTV-PyMT mouse model for mammary carcinoma (FVB/n background) and the RIP1-Tag2 mouse model for pancreatic neuroendocrine carcinoma (C57BL/6 background). Mice are treated daily by intra-peritoneal injections of the PAD4 inhibitor GSK484 (4 mg/kg). GSK484 is dissolved in 99.9% ethanol at a concentration of 25 mg/mL to generate a stock solution and further diluted 1:50 in 0.9% NaCl shortly before injection of 200 μL/mouse[2].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

References
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Product Name:
GSK484 hydrochloride
Cat. No.:
HY-100514
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