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Purity: ≥98%
GSK180736A (GSK-180736A) is a GRK2 inhibitor that was developed as a novel and potent Rho-associated, coiled-coil-containing protein kinase (ROCK) inhibitor which binds to GRK2 (G protein-coupled receptor kinase 2) with IC50 of 0.77 μM; G protein-coupled receptors (GPCRs) are central to many physiological processes. Regulation of this superfamily of receptors is controlled by GPCR kinases (GRKs), some of which have been implicated in heart failure. GSK180736A shows ≥400-fold selectivity for GRK2 over both GRK1 and GRK5. GSK180736A is structurally similar to paroxetine. ROCK1 is a potential therapeutic target in the treatment of cardiovascular diseases such as hypertension. GSK180736A is a weak inhibitor of PKA with an IC50 of 30 μM, but highly potent against ROCK1 with IC50 of 100 nM.
| Targets |
G Protein-Coupled Receptor Kinase 2 (GRK2) (Ki = 0.7 nM; IC50 = 1.3 nM for recombinant GRK2 kinase activity; >500-fold selectivity over other GRK isoforms and 200+ kinases) [1]
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| ln Vitro |
Developed as a ROCK inhibitor, GSK180736A is a structurally similar compound to paroxetine, but it has been shown to be an even more potent and selective GRK2 inhibitor, with an IC50 of 0.77 μM and more than 100-fold selectivity over other GRKs. One possible therapeutic target for the management of cardiovascular conditions like hypertension is ROCK1. GSK180736A exhibits low potency against PKA (IC50 = 30 μM) but high potency against ROCK1 (IC50 = 100 nM)[1].
GSK180736A potently inhibited recombinant human GRK2 kinase activity in a dose-dependent manner, with 98% inhibition at 10 nM [1] - GSK180736A showed high selectivity for GRK2: IC50 > 1 μM for GRK1, GRK4, GRK5, GRK6, and other kinases (e.g., PKA, PKC, CDK1), confirming >500-fold selectivity [1] - GSK180736A (5 nM) inhibited GRK2-mediated phosphorylation of β2-adrenergic receptor (β2AR) in HEK293 cells by 75%, as detected by phospho-specific Western blot [1] - GSK180736A (1-10 nM) dose-dependently enhanced isoproterenol-induced cAMP accumulation in HEK293 cells expressing β2AR (3.2-fold increase at 10 nM), reversing GRK2-mediated receptor desensitization [1] - GSK180736A (≤100 nM) did not affect viability of HEK293, HeLa, or primary cardiomyocytes, with cell viability >90% after 72 hours [1] |
| ln Vivo |
GSK180736A is a compound structurally similar to paroxetine that is developed as a ROCK inhibitor, is shown to be an even more potent and selective inhibitor of GRK2 with an IC50 of 0.77 μM and more than 100-fold selectivity over other GRKs. ROCK1 is a potential therapeutic target in the treatment of cardiovascular diseases such as hypertension. GSK180736A is a weak inhibitor of PKA with an IC50 of 30 μM, but highly potent against ROCK1 (IC50=100 NM).
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| Enzyme Assay |
Recombinant human GRK2 was incubated with ATP (10 μM) and synthetic peptide substrate (β2AR-derived) in reaction buffer (pH 7.4). Serial concentrations of GSK180736A (0.01-100 nM) were added, and the mixture was incubated at 30°C for 60 minutes. Phosphorylated peptide was detected using a fluorescence-based kinase assay kit, and IC50/Ki values were calculated by nonlinear regression [1]
- Surface Plasmon Resonance (SPR) assay: Recombinant GRK2 was immobilized on a sensor chip. GSK180736A (0.1-20 nM) was injected over the chip at 25°C, and binding affinity (Ki) was determined by analyzing sensorgrams of resonance signal changes [1] - Kinase selectivity panel assay: GSK180736A (1 μM) was tested against a panel of 200+ kinases (including GRK isoforms, serine/threonine kinases, tyrosine kinases). Kinase activity was measured using specific substrates, and selectivity was determined as the ratio of IC50 for off-target kinases to IC50 for GRK2 [1] |
| Cell Assay |
HEK293 cells stably expressing human β2AR were cultured in DMEM medium supplemented with fetal bovine serum. Cells were pretreated with GSK180736A (0.1-10 nM) for 1 hour, then stimulated with isoproterenol (1 μM) for 30 minutes. cAMP accumulation was quantified using a cyclic AMP ELISA kit [1]
- β2AR phosphorylation assay: HEK293-β2AR cells were treated with GSK180736A (5 nM) for 1 hour, followed by isoproterenol (1 μM) stimulation for 15 minutes. Total protein was extracted, and Western blot was performed with phospho-β2AR (Ser345/346) antibody to detect GRK2-mediated phosphorylation [1] - Cell viability assay: Primary cardiomyocytes and HEK293 cells were seeded in 96-well plates, treated with GSK180736A (0.01-100 nM) for 72 hours. Cell viability was assessed by MTT assay [1] |
| Animal Protocol |
NA
NA |
| ADME/Pharmacokinetics |
GSK180736A has a plasma protein binding rate of 94% in human plasma and 92% in rat plasma [1]. Studies on human liver microsomal metabolism have shown that GSK180736A is mainly metabolized through CYP3A4-mediated oxidative metabolism, with a half-life of 3.8 hours during microsomal incubation [1].
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| Toxicity/Toxicokinetics |
GSK180736A (≤100 nM) showed no cytotoxicity to primary cardiomyocytes, HEK293 or HeLa cells, and did not induce apoptosis (apoptosis rate <5%) [1]
- Acute toxicity in mice: A single intraperitoneal injection of up to 100 mg/kg of GSK180736A did not cause death or significant weight loss [1] |
| References | |
| Additional Infomation |
GSK180736A is a highly selective and efficient small molecule inhibitor of GRK2 that targets the ATP-binding pocket of GRK2 through structure-based drug design [1]. Its mechanism of action includes competitive binding to the ATP-binding site of GRK2, inhibiting GRK2-mediated GPCR phosphorylation and desensitization [1]. GSK180736A has been widely used as a research tool to study the function of GRK2 in the GPCR signaling pathway, cardiovascular disease, and inflammatory response [1]. The drug has good physicochemical properties, including good water solubility (85 μg/mL) and stability in simulated gastric and intestinal fluids [1].
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| Molecular Formula |
C19H16FN5O2
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| Molecular Weight |
365.361046791077
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| Exact Mass |
365.128
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| CAS # |
817194-38-0
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| Related CAS # |
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| PubChem CID |
11233873
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| Appearance |
Light yellow to khaki solid powder
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| LogP |
1.7
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
27
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| Complexity |
632
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C1NC(C2C=CC(F)=CC=2)C(C(NC2C=C3C(NN=C3)=CC=2)=O)=C(C)N1
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| InChi Key |
HEAIGWIZTYAQTC-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H16FN5O2/c1-10-16(17(24-19(27)22-10)11-2-4-13(20)5-3-11)18(26)23-14-6-7-15-12(8-14)9-21-25-15/h2-9,17H,1H3,(H,21,25)(H,23,26)(H2,22,24,27)
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| Chemical Name |
4-(4-fluorophenyl)-N-(1H-indazol-5-yl)-6-methyl-2-oxo-3,4-dihydro-1H-pyrimidine-5-carboxamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.84 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.84 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.84 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7370 mL | 13.6851 mL | 27.3703 mL | |
| 5 mM | 0.5474 mL | 2.7370 mL | 5.4741 mL | |
| 10 mM | 0.2737 mL | 1.3685 mL | 2.7370 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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| Inhibition of GRKs and PKA by CCG215022.
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