GSK046

For research use only.

Catalog No.S9684 Synonyms: iBET-BD2

GSK046 Chemical Structure

CAS No. 2474876-09-8

GSK046 (iBET-BD2) is a selective and orally active inhibitor of BET (bromodomain and extraterminal domain) with IC50 of 264 nM, 98 nM, 49 nM and 214 nM for BRD2BD2, BRD3BD2, BRD4BD2 and BRDTBD2, respectively. GSK046 exhibits immunomodulatory activity.

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Biological Activity

Description GSK046 (iBET-BD2) is a selective and orally active inhibitor of BET (bromodomain and extraterminal domain) with IC50 of 264 nM, 98 nM, 49 nM and 214 nM for BRD2BD2, BRD3BD2, BRD4BD2 and BRDTBD2, respectively. GSK046 exhibits immunomodulatory activity.
Targets
BRD4BD2 [1]
(Cell-free assay)
BRD3BD2 [1]
(Cell-free assay)
BRDTBD2 [1]
(Cell-free assay)
BRD2BD2 [1]
(Cell-free assay)
49 nM 98 nM 214 nM 264 nM
In vitro

GSK046 shows an excellent level of selectivity for the BET family with no measurable activity for non-BET bromodomains. GSK046 is tested in an LPS-stimulated peripheral blood mononuclear cell (PBMC) cellular assay. After stimulation, these immune cells release a range of cytokines and chemokines, including monocyte chemoattractant protein 1 (MCP-1/CCL2). GSK046 also inhibits MCP-1 production (pIC50 = 7.5) with a minimal drop-off from the biochemical BRD4 BD2 potency observed.[2]

In vivo

GSK046 has suitable physicochemical and pharmacokinetic properties to be utilized in vivo, and it has also been demonstrated that a highly selective BD2 inhibitor retains the ability to potently inhibit MCP-1 cytokine release in a cellular and whole blood context. GSK046 proves useful for further biological profiling. GSK046 is efficacious in a broad range of inflammatory pathologies and selective BD2 inhibition may be a useful new therapeutic strategy for immunoinflammatory diseases.[2]

Protocol

Cell Research:

[2]

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  • Cell lines: PBMCs, hepatocytes
  • Concentrations: 0.5 μM
  • Incubation Time: 5 min, 10 min, 20 min, 40 min, 60 min, 120 min
  • Method:

    The metabolic stability of GSK046 is tested in male Wistar Han rat, male Beagle dog and mixed gender pooled human hepatocytes. Suspensions of cryopreserved hepatocytes from each species are used. Incubations are performed at a test or control compound concentration of 0.5 μM at 37 °C, at a cell density of 0.5 million viable cells/mL. Control incubations are also performed in lysed cells to reveal any non-enzymatic degradation. For Rat and Human incubation samples (50 μL) are removed from the incubation mixture at 0, 5, 10, 20, 40 and 60 min. For Dog incubation samples (50 μL) are removed from the incubation mixture at 0, 10, 20, 40, 60 and 120 min. The samples are added to methanol, containing internal standard, (100 μL) to stop the reaction. Following protein precipitation, the compound remaining in the supernatants is measured using specific LC-MS/MS methods as a ratio to the internal standard in the absence of a calibration curve. Peak area ratios (Compound to IS) are fitted to an unweighted logarithmic decline in substrate. Using the first order rate constant, clearance is calculated by adjustment for protein concentration, volume of the incubation and hepatic scaling factor.


    (Only for Reference)
Animal Research:

[2]

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  • Animal Models: male Wistar Han Rats, male Beagle dogs
  • Dosages: 0.5 mg/kg, 1 mg/kg, 3 mg/kg
  • Administration: IV, Oral gavage
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 83 mg/mL (200.25 mM)
Water Insoluble
Ethanol '83 mg/mL

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 414.47
Formula

C23H27FN2O4

CAS No. 2474876-09-8
Storage powder
in solvent
Synonyms iBET-BD2

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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

Tel: +1-832-582-8158 Ext:3

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID