| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 5mg |
|
||
| 50mg | |||
| Other Sizes |
| Targets |
Spleen tyrosine kinase (SYK). GSK2646264 is a potent and specific inhibitor of SYK with a pIC50 of 7.1.
|
|---|---|
| ln Vitro |
In a concentration-dependent manner, GSK2646264 (0.01-10 μM; 1 h) significantly inhibits the release of histamine from skin mast cells induced by anti-IgE, but not by C5a. 6.8 μM is the IC90 and 0.7 μM is the IC50[2]. In isolated human skin mast cells, GSK2646264 cream (0.5%, 1%, and 3% [wt/wt]; 1 cm2; 4 and 24 hours) inhibits anti-IgE-induced histamine release [2].
GSK2646264 inhibits SYK with a pIC50 of 7.1 (IC50 ≈ 79 nM). It has >300-fold selectivity over Aurora B. GSK2646264 inhibits anti-IgM induced Erk1/2 phosphorylation in Ramos B cells with a pIC50 of 6.7. It also inhibits other kinases with pIC50s of 5.4 (LCK, LRRK2), 5.3 (GSK3β), 5 (JAK2), 4.5 (VEGFR2), <4.6 (Aurora B), and <4.3 (Aurora A). The compound possesses a distinct selectivity fingerprint that differentiates it from both systemic and other topical SYK-targeting agents. |
| ln Vivo |
In vivo, GSK2646264 can penetrate the epidermal and dermal layers of the skin, making it suitable for topical application. The compound has been evaluated in a double-blind, multicentre, Phase Ib study for active cutaneous lupus erythematosus (CLE) lesions. The study assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical efficacy. GSK2646264 has also been studied in subjects with chronic spontaneous urticaria and in healthy subjects following provocation tests. A First Time in Human (FTIH) study is evaluating the short-term effects of GSK2646264 on the number and size of weals.
|
| Enzyme Assay |
SYK kinase activity is assessed using in vitro kinase assays with recombinant SYK enzyme and a peptide substrate. Radiolabeled ATP or luminescent-based assays (e.g., ADP-Glo) are used to measure kinase activity. pIC50 values are calculated from dose-response curves using nonlinear regression analysis. Selectivity is evaluated by profiling against a panel of kinases including LCK, LRRK2, GSK3β, JAK2, VEGFR2, Aurora A, and Aurora B.
|
| Cell Assay |
Cellular activity is evaluated in Ramos B cells or other SYK-dependent cell lines. Cells are treated with GSK2646264 at various concentrations (typically 0.001-100 μM) for appropriate time periods (15-60 minutes for signaling assays). Anti-IgM induced Erk1/2 phosphorylation is measured by Western blot using phospho-specific antibodies (pERK1/2) and total ERK1/2 as loading control. B-cell receptor signaling is assessed by measuring phosphorylation of SYK, BLNK, and PLCγ2 by Western blot. Cytokine production (e.g., IL-6, TNFα) may be measured by ELISA from cell culture supernatants. Cell proliferation is assessed by MTT or CellTiter-Glo assays.
|
| Animal Protocol |
In vivo efficacy is studied in animal models of inflammatory skin diseases, cutaneous lupus erythematosus, and chronic spontaneous urticaria. GSK2646264 is administered topically (as a cream or gel formulation) or via intradermal injection. Skin penetration is assessed by measuring compound concentrations in skin layers (stratum corneum, epidermis, dermis) by LC-MS/MS. In CLE models, skin lesion severity is scored, and skin biopsies are analyzed for inflammatory infiltrates (immunohistochemistry), interferon-related gene expression (qRT-PCR), and SYK phosphorylation (Western blot, immunohistochemistry). In urticaria models, weal and flare responses are measured. Pharmacodynamic markers include SYK phosphorylation status and downstream signaling in skin biopsies. Clinical trials in CLE patients assess safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical efficacy.
|
| ADME/Pharmacokinetics |
GSK2646264 has a molecular formula of C19H21ClN6O2 and a molecular weight of 400.86 g/mol. CAS Number: 1398695-47-0. It is a potent and selective SYK inhibitor. Purity: typically ≥98% by HPLC. The compound is soluble in DMSO and should be stored at -20°C for long-term stability, protected from light and moisture. Detailed pharmacokinetic parameters including skin penetration, half-life, and bioavailability are available from preclinical and clinical studies.
|
| Toxicity/Toxicokinetics |
Safety data for GSK2646264 are available from clinical trials. In a double-blind, multicentre, Phase Ib study, the safety and tolerability of GSK2646264 in active CLE lesions were evaluated. As a kinase inhibitor, it may have off-target effects. The compound is for research use only and has been investigated in clinical development for inflammatory skin diseases. Standard laboratory safety practices should be followed, including the use of personal protective equipment and biological safety cabinets. Consult the material safety data sheet (MSDS) for detailed safety information.
|
| References |
|
| Additional Infomation |
GSK2646264 is a research tool compound for studying SYK biology and B-cell receptor signaling. It is not approved for clinical use. The compound has been investigated for its potential in inflammatory skin diseases (cutaneous lupus erythematosus) and chronic spontaneous urticaria. GSK2646264 can penetrate the epidermal and dermal layers of the skin, suggesting potential for topical applications. It possesses a distinct selectivity fingerprint, dermal pharmacokinetic profile, and ex vivo functional potency that directly differentiate it from both systemic and other topical SYK-targeting agents. The compound is being evaluated in clinical trials including a Phase Ib study in CLE and a First Time in Human study in CsU.
|
| Molecular Formula |
C24H26N2O2
|
|---|---|
| Molecular Weight |
374.484
|
| Exact Mass |
374.199
|
| CAS # |
1398695-47-0
|
| Related CAS # |
1398695-49-2 (sulfate);1398695-47-0;
|
| PubChem CID |
60194098
|
| Appearance |
White to off-white solid powder
|
| Density |
1.1±0.1 g/cm3
|
| Boiling Point |
517.4±50.0 °C at 760 mmHg
|
| Flash Point |
266.7±30.1 °C
|
| Vapour Pressure |
0.0±1.3 mmHg at 25°C
|
| Index of Refraction |
1.585
|
| LogP |
3.4
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
4
|
| Rotatable Bond Count |
5
|
| Heavy Atom Count |
28
|
| Complexity |
474
|
| Defined Atom Stereocenter Count |
0
|
| InChi Key |
KYANYGKXMNYFBX-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C24H26N2O2/c1-17-8-13-26-21(14-17)16-28-23-5-3-4-22(27-2)24(23)20-7-6-18-9-11-25-12-10-19(18)15-20/h3-8,13-15,25H,9-12,16H2,1-2H3
|
| Chemical Name |
7-[2-methoxy-6-[(4-methylpyridin-2-yl)methoxy]phenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine
|
| Synonyms |
GSK 2646264 GSK-2646264 GSK2646264
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO : ~50 mg/mL (~133.52 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.25 mg/mL (3.34 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 12.5 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: ≥ 1.25 mg/mL (3.34 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 12.5 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: ≥ 1.25 mg/mL (3.34 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 | 2.6704 mL | 13.3518 mL | 26.7037 mL | |
| 5 mM | 0.5341 mL | 2.6704 mL | 5.3407 mL | |
| 10 mM | 0.2670 mL | 1.3352 mL | 2.6704 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
