GSK046 (iBET-BD2)

Catalog No.S9684 Batch:S968401

Technical Data

Formula	C₂₃H₂₇FN₂O₄
Molecular Weight	414.47	CAS No.	2474876-09-8
Solubility (25°C)*	In vitro	DMSO	83 mg/mL (200.25 mM)
		Ethanol	83 mg/mL (200.25 mM)
		Water	Insoluble
* <1 mg/ml means slightly soluble or insoluble. * 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. * Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

Preparing Stock Solutions

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 BRD2_BD2, BRD3_BD2, BRD4_BD2 and BRDT_BD2, respectively. GSK046 exhibits immunomodulatory activity.

Targets

BRD4_BD2 ^[1] (Cell-free assay)	BRD3_BD2 ^[1] (Cell-free assay)	BRDT_BD2 ^[1] (Cell-free assay)	BRD2_BD2 ^[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 (from reference)

Cell Assay:^{^[2]}	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.
Animal Study:^{^[2]}	Animal Models male Wistar Han Rats, male Beagle dogs Dosages 0.5 mg/kg, 1 mg/kg, 3 mg/kg Administration IV, Oral gavage

Cell Assay:^{^[2]}

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.

Animal Study:^{^[2]}

Animal Models
male Wistar Han Rats, male Beagle dogs
Dosages
0.5 mg/kg, 1 mg/kg, 3 mg/kg
Administration
IV, Oral gavage

References

RETURN POLICY
Selleck Chemical’s Unconditional Return Policy ensures a smooth online shopping experience for our customers. If you are in any way unsatisfied with your purchase, you may return any item(s) within 7 days of receiving it. In the event of product quality issues, either protocol related or product related problems, you may return any item(s) within 365 days from the original purchase date. Please follow the instructions below when returning products.

SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

NOT FOR HUMAN, VETERINARY DIAGNOSTIC OR THERAPEUTIC USE.