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| Targets |
GSK046 targets the BD2 bromodomains of the BET proteins (BRD2, BRD3, BRD4, and BRDT). It is a highly selective inhibitor for the BD2 domain over the BD1 domain. By inhibiting the BD2 domain, GSK046 modulates the interaction of BET proteins with acetylated histones, thereby affecting gene transcription.
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| ln Vitro |
Following IFN-γ stimulation, GSK046 (1000 nM; updated every three days) decreases the recruitment of BET proteins to interferon (IFN) target genes. Compared to BRD4, GSK046 seems to have a greater impact on BRD2 and BRD3 recruitment[1]. In B and T cell co-culture systems, GSK046 (0.1-10 μM) has a more specific phenotypic fingerprint, blocking critical genes for the generation of pro-inflammatory mediators, including Th17 cytokines [1]. GSK046 (0.01-10 μM; 72 hours) reduces the production of effector cytokines such as IFNγ, IL-17A, and IL-22, but does not impact the proliferative activity of human primary CD4+ T cells [1]. Without compromising cell viability, GSK046 (0.005–10 μM; 48 hours) reduces macrophage activation following PMA stimulation [1].
In vitro, GSK046 (1000 nM) decreases the recruitment of BET proteins to interferon (IFN) target genes following IFN-γ stimulation. In B and T cell co-culture systems, GSK046 (0.1-10 μM) blocks critical genes for the generation of pro-inflammatory mediators, including Th17 cytokines. It reduces the production of effector cytokines such as IFNγ, IL-17A, and IL-22, but does not impact the proliferative activity of human primary CD4+ T cells. |
| ln Vivo |
Immunomodulatory action is exhibited by GSK046 (40 mg/kg/QD; subcutaneous injection over 14 days) [1]. Following oral dosing (C57BL6 10, C57B16 40 mg/kg), GSK046 displays a Cmax (C57BL6 1589, C57B16 2993 ng/mL) and terminal elimination half-life (C57BL6 1.8, C57B16 1.9 hours) [1]. Following oral treatment (mouse 10 mg/kg, rat 10 mg/kg), GSK046 displays a Cmax of 1589 ng/mL and a terminal elimination half-life of 1.8 and 1.4 hours, respectively [1].
In vivo, GSK046 exhibits immunomodulatory action. Following oral dosing in mice (C57BL6 10 mg/kg), it displays a Cmax of 1589 ng/mL and a terminal elimination half-life of 1.8 hours. In a mouse model, subcutaneous injection of GSK046 (40 mg/kg/QD for 14 days) decreased the production of anti-keyhole limpet hemocyanin (KLH) IgM and was well tolerated. |
| Enzyme Assay |
The in vitro assay for GSK046 involves measuring its effect on cytokine production. Human primary CD4+ T cells are treated with GSK046 at concentrations of 0.001, 0.01, 0.1, 1, and 10 μM for 72 hours. The production of effector cytokines such as IFNγ, IL-17A, and IL-22 is measured, while cell proliferation is also assessed.
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| Cell Assay |
Cell Proliferation Assay[1]
Cell Types: Human primary CD4+ T cell Tested Concentrations: 0.001, 0.01, 0.1, 1, 10 μM Incubation Duration: 72 hrs (hours) Experimental Results: Did not affect the proliferative activity of the cells but still inhibited the production of effector cytokines . Cellular assays for GSK046 are performed using human primary CD4+ T cells in B and T cell co-culture systems. Cells are treated with GSK046 (0.1-10 μM). The compound's effect on the generation of pro-inflammatory mediators, including Th17 cytokines, is assessed. Macrophage activation following PMA stimulation is also evaluated (0.005–10 μM; 48 hours). |
| Animal Protocol |
Animal/Disease Models: Male C57BL/6 mice (8/10-weeks-old) are injected with keyhole limpet hemocyanin (KLH)[1]
Doses: 40 mg/kg/QD Route of Administration: Sc injections for 14 days Experimental Results: decreased the production of anti-keyhole limpet hemocyanin (KLH) IgM and was well tolerated. Animal/Disease Models: Female C57BL/6 mice[1] Doses: 10 mg/kg (pharmacokinetic/PK Analysis) Route of Administration: Oral administration Experimental Results: Cmax (1859 ng/mL), T1 /2 (1.8 h). Animal/Disease Models: Male C57BL/6 mice[1] Doses: 40 mg/kg (pharmacokinetic/PK Analysis) Route of Administration: Oral administration Experimental Results: Cmax (2993 ng/mL), T1/2 (1.9 h). Animal/Disease Models: Female Lewis rat[1] Doses: 10 mg/kg (pharmacokinetic/PK Analysis) Route of Administration: Oral administration Experimental Results: Cmax (202 ng/mL), T1/2 (1.4 h). In vivo animal studies for GSK046 are conducted in male C57BL/6 mice (8/10-weeks-old) injected with keyhole limpet hemocyanin (KLH). The compound is administered via subcutaneous injection at 40 mg/kg/QD for 14 days. The production of anti-KLH IgM is measured to assess immunomodulatory effects. Pharmacokinetic studies are also performed in female C57BL/6 mice at 10 mg/kg. |
| ADME/Pharmacokinetics |
GSK046 is an orally active compound with favorable pharmacokinetic properties. In mice, it displays a Cmax of 1589 ng/mL and a terminal elimination half-life of 1.8 hours at a 10 mg/kg dose. The compound is well tolerated in animal models. Specific PK parameters such as bioavailability and volume of distribution have not been detailed.
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| Toxicity/Toxicokinetics |
Toxicity data for GSK046 are not extensively detailed. In animal studies, it was well tolerated at doses up to 40 mg/kg/QD for 14 days. The compound does not affect the proliferative activity of human primary CD4+ T cells, indicating a favorable safety profile. Specific toxicological profiles have not been characterized.
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| References | |
| Additional Infomation |
4-(acetylamino)-3-fluoro-N-(trans-4-hydroxycyclohexyl)-5-[(1S)-1-phenylethoxy]benzamide is a secondary amide formed by the condensation of the carboxyl group of 4-acetylamino-3-fluoro-5-[(1S)-1-phenylethoxy]benzoic acid with the amino group of trans-4-aminocyclohexanol. It is a potent pan-BD2 bromodomain inhibitor. It can function as an inhibitor of bromodomain-containing protein 4 and as an antitumor drug. It is a secondary amide belonging to the acetamide, benzamide, benzene, cyclohexanol, aromatic ether, and monofluorobenzene classes.
GSK046 is a research compound used as a chemical probe to study the function of BET protein BD2 domains. It is a potent and selective inhibitor with immunomodulatory activity. The compound is available from commercial suppliers for research use only. It is not approved for human therapeutic use. |
| Molecular Formula |
C23H27FN2O4
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|---|---|
| Molecular Weight |
414.4699
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| Exact Mass |
414.195
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| CAS # |
2474876-09-8
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| PubChem CID |
146018690
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| Appearance |
White to off-white solid powder
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| LogP |
3
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
30
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| Complexity |
576
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| Defined Atom Stereocenter Count |
1
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| SMILES |
FC1C(=C(C([H])=C(C=1[H])C(N([H])C1([H])C([H])([H])C([H])([H])C([H])(C([H])([H])C1([H])[H])O[H])=O)O[C@@]([H])(C([H])([H])[H])C1C([H])=C([H])C([H])=C([H])C=1[H])N([H])C(C([H])([H])[H])=O
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| InChi Key |
FRBRZGLUFOZRGD-YCMKEVRSSA-N
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| InChi Code |
InChI=1S/C23H27FN2O4/c1-14(16-6-4-3-5-7-16)30-21-13-17(12-20(24)22(21)25-15(2)27)23(29)26-18-8-10-19(28)11-9-18/h3-7,12-14,18-19,28H,8-11H2,1-2H3,(H,25,27)(H,26,29)/t14-,18?,19?/m0/s1
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| Chemical Name |
4-acetamido-3-fluoro-N-(4-hydroxycyclohexyl)-5-[(1S)-1-phenylethoxy]benzamide
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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 |
| 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) |
DMSO : ~83.33 mg/mL (~201.05 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.02 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 20.8 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: ≥ 2.08 mg/mL (5.02 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 20.8 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: ≥ 2.08 mg/mL (5.02 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 | 2.4127 mL | 12.0636 mL | 24.1272 mL | |
| 5 mM | 0.4825 mL | 2.4127 mL | 4.8254 mL | |
| 10 mM | 0.2413 mL | 1.2064 mL | 2.4127 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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