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| Targets |
GSK-778 targets the BD1 bromodomain of BET proteins, including BRD2, BRD3, BRD4, and BRDT. BET proteins are epigenetic readers that recognize acetylated lysine residues on histone tails and regulate gene transcription. The BD1 and BD2 bromodomains of BET proteins have distinct functions, with BD1 being primarily responsible for recognizing acetylated histones. By selectively inhibiting BD1, GSK-778 disrupts the binding of BET proteins to acetylated chromatin, leading to changes in gene expression. The compound's selectivity for BD1 over BD2 makes it a valuable tool for studying the specific roles of each bromodomain in BET protein function.
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| ln Vitro |
At IC50s of 3950 nM for BRD2 BD2, 1210 nM for BRD3 BD2, 5843 nM for BRD4 BD2, and 17451 nM for BRDDT BD2, GSK778 inhibits BRD BD2 [1]. Human primary CD4+ T cell proliferation and the generation of effector cytokines, such as IFNγ, IL-17A, and IL-22, are inhibited by GSK778 (0.01-10 μM; 72 hours) [1]. The effect of GSK778 (0.001-10 μM; 5 days) on the proliferation and viability of MDA-453, MOLM-13, K562, MV4-11, THP-1, and MDA-MB-231 cells is more pronounced [1]. For MV4-11, MOLM13, MDA-MB-231, and MB453 cells, GSK778 (1000 nM; 72 hours) suppresses proliferation and causes cell cycle arrest as well as apoptosis [1]. Primary human AML cells' ability to proliferate is inhibited by GSK778 (1000 nM; 12 days) [1].
In vitro, GSK-778 demonstrates potent inhibition of BD1 bromodomains with IC50 values in the low nanomolar range. The compound inhibits proliferation in cancer cells, phenocopying the effects of pan-BET inhibitors. GSK-778's selectivity for BD1 over BD2 allows researchers to distinguish between the contributions of the two bromodomains to BET protein function. The compound shows activity in various cancer cell lines, consistent with the role of BET proteins in regulating oncogenic gene expression. In vivo data for GSK-778 is limited in the available literature. The compound is primarily used as a research tool for in vitro studies of epigenetic regulation and cancer biology. GSK-778's ability to phenocopy the effects of pan-BET inhibitors suggests that it may have similar in vivo activity, but specific in vivo efficacy data has not been extensively reported. |
| ln Vivo |
GSK778 (15mg/kg/BID; i.p. for 30 days) has a higher survival benefit than iBET-BD2 in the aggressive MLL-AF9 AML model [1]. ?GSK778 (15 mg/kg/BID; subcutaneously for 14 days) lowers the generation of anti-keyhole limpet hemocyanin (KLH) IgM and is well tolerated [1]. ?GSK778 demonstrates Cmax (85 ng/mL), Tmax (1.48 h) and AUC∞ (132 ng.h/mL) after oral treatment (10mg/kg) to mice [1].
GSK-778's inhibition of BD1 bromodomains is assessed using biochemical binding assays. AlphaScreen or TR-FRET (time-resolved fluorescence resonance energy transfer) assays are used to measure the binding of GSK-778 to recombinant BD1 domains of BET proteins. In these assays, a biotinylated acetylated histone peptide is used as the substrate, and the displacement of a labeled BET BD1 domain by GSK-778 is measured. IC50 values are calculated from dose-response curves. Selectivity for BD1 over BD2 is assessed by comparing IC50 values for BD1 and BD2 domains of the same BET protein. These assays provide quantitative information on the potency and selectivity of GSK-778. |
| Enzyme Assay |
GSK-778 is tested on cultured cancer cells to assess its effects on proliferation and gene expression. Cells are treated with varying concentrations of GSK-778; cell proliferation is assessed by MTT or CellTiter-Glo assays; gene expression changes are assessed by RNA-seq or qPCR for BET target genes (e.g., MYC, BCL2); histone acetylation and BET protein binding are assessed by ChIP-seq or ChIP-qPCR. These cell-based assays demonstrate the mechanism of action and antiproliferative activity of GSK-778.
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| Cell Assay |
Cell proliferation assay [1]
Cell Types: Human primary CD4+ T cells Tested Concentrations: 0.001, 0.01, 0.1, 1, 10 μM Incubation Duration: 72 hrs (hours) Experimental Results: Inhibited cell proliferative activity and effector cytokine production. Cell viability assay[1] Cell Types: MDA-453, MOLM-13, K562, MV4-11, THP-1 and MDA-MB-231 Cell Tested Concentrations: 0.001, 0.01, 0.1, 1, 10 μM Incubation Duration: 5 days Experimental Results: Inhibition of growth and viability of human cancer cell lines. Apoptosis analysis[1] Cell Types: MV4-11, MOLM13, MDA-MB-231 and MB453 Cell Tested Concentrations: 1000 nM Incubation Duration: 72 hrs (hours) Experimental Results: Inhibited cell proliferation and induced cell cycle arrest and apoptosis. Animal studies for GSK-778 are limited in the available literature. The compound has not been extensively evaluated in vivo, and specific animal models, dosing regimens, and efficacy endpoints have not been reported. GSK-778 is primarily used as a research tool for in vitro studies. Further studies are needed to characterize the in vivo activity of GSK-778. |
| Animal Protocol |
Animal/Disease Models: Female C57BL/6 mice 6-8 weeks old were injected with MLL-AF9 cells [1].
Doses: 15 mg/kg/BID. Route of Administration: intraperitoneal (ip) injection for 30 days. Experimental Results: Improved survival rate of leukemia mice. Animal/Disease Models: Male CD1 mice [1] Doses: 10 mg/kg (pharmacokinetic/PK/PK analysis) Route of Administration: Oral administration Experimental Results: Cmax (85 ng/mL), Tmax (1.48 h); AUC∞ (132 ng.h/mL). Pharmacokinetic data for GSK-778 is not available in the literature. The compound is used primarily in research settings for in vitro studies. As a small molecule inhibitor, GSK-778 is expected to have properties suitable for cellular penetration, but its absorption, distribution, metabolism, and excretion have not been characterized. |
| ADME/Pharmacokinetics |
Toxicological data for GSK-778 is not available in the literature. The compound is used in research settings and has not been evaluated for clinical safety. As a BET inhibitor, GSK-778 may have effects on normal cells as well as cancer cells, and its toxicity profile would need to be characterized in future studies.
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| Toxicity/Toxicokinetics |
GSK-778 (iBET-BD1) is a potent and selective BD1 bromodomain inhibitor of BET proteins, with IC50 values of 75 nM (BRD2 BD1), 41 nM (BRD3 BD1), 41 nM (BRD4 BD1), and 143 nM (BRDT BD1). The compound is a chemical probe that phenocopies the effects of pan-BET inhibitors in cancer models, but with selectivity for the BD1 domain over the BD2 domain. GSK-778 is used as a research tool for studying the specific roles of BD1 and BD2 bromodomains in BET protein function and for investigating epigenetic regulation in cancer biology. The compound inhibits proliferation in cancer cells and is a valuable tool for dissecting the mechanisms of BET inhibitor activity. GSK-778 is not approved as a therapeutic agent and is used for research purposes only.
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| References |
| Molecular Formula |
C30H33N5O3
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|---|---|
| Molecular Weight |
511.6147
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| Exact Mass |
511.258
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| CAS # |
2451862-42-1
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| PubChem CID |
146018691
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| Appearance |
White to light yellow solid powder
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| LogP |
4.2
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
38
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| Complexity |
768
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| Defined Atom Stereocenter Count |
2
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| SMILES |
O(C1=C(C2C(C([H])([H])[H])=NOC=2C([H])([H])[H])C([H])=C2C(=C1[H])C1=C(C([H])=N2)N=C(C([H])([H])OC([H])([H])[H])N1[C@]([H])(C([H])([H])[H])C1C([H])=C([H])C([H])=C([H])C=1[H])C([H])([H])[C@]1([H])C([H])([H])N([H])C([H])([H])C1([H])[H]
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| InChi Key |
ZORLJXWXFABTPZ-CTNGQTDRSA-N
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| InChi Code |
InChI=1S/C30H33N5O3/c1-18-29(20(3)38-34-18)24-12-25-23(13-27(24)37-16-21-10-11-31-14-21)30-26(15-32-25)33-28(17-36-4)35(30)19(2)22-8-6-5-7-9-22/h5-9,12-13,15,19,21,31H,10-11,14,16-17H2,1-4H3/t19-,21+/m1/s1
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| Chemical Name |
4-[2-(methoxymethyl)-1-[(1R)-1-phenylethyl]-8-[[(3S)-pyrrolidin-3-yl]methoxy]imidazo[4,5-c]quinolin-7-yl]-3,5-dimethyl-1,2-oxazole
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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 : ~41.67 mg/mL (~81.45 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.07 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 (4.07 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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 (4.07 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 | 1.9546 mL | 9.7731 mL | 19.5461 mL | |
| 5 mM | 0.3909 mL | 1.9546 mL | 3.9092 mL | |
| 10 mM | 0.1955 mL | 0.9773 mL | 1.9546 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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