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GSK046 (iBET-BD2), BD2 bromodomain inhibitor of the BET proteins with immunomodulatory activity. It inhibitsBETproteins withIC50s of 264 nM (BRD2 BD2), 98 nM (BRD3 BD2), 49 nM (BRD4 BD2) and 214 nM (BRDT BD2), respectively.
| 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].
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| 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].
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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 . |
| 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). |
| References |
| Molecular Formula |
C23H27FN2O4
|
|---|---|
| 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
|
| 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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