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Purity: ≥98%
I-BET151 (also known as GSK-1210151A) is a novel, potent and selective BET (Bromodomain and extra terminal domain) inhibitor with anticancer activity. It inhibits BRD2, BRD3 and BRD4 with IC50s of 0.5 μM, 0.25 μM, and 0.79 μM in cell-free assays, respectively. I-BET151 has the similar inhibition function as TMZ. When tested with 6 myeloma cell lines, I-BET151 treatment decreased cells percent in S/G2 phase and increased cell apoptosis in a time- and dose- dependent manner. In globlastoma cell line U87MG, administration of I-BET151 arrested cells in the G1 phase and reduced cell proliferation ability.
| Targets |
BRD4 (pIC50 = 6.1); BRD2 (pIC50 = 6.3); BRD3 (pIC50 = 6.6)[1]
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|---|---|
| ln Vitro |
I-BET151 (1 μM; 72 hours) treatment demonstrated that the majority of viable cells were in G0 phase, congruent with dose- and time-dependent decreases in cell proliferation and elimination of bromodeoxyuridine accumulation [2]. I-BET151 (100 nM; 72 hours) causes a dose- and time-dependent decrease in the fraction of S/G2 phase myeloma cells [2].
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| ln Vivo |
I-BET151 shows good oral systemic exposure and low blood clearance (roughly 20% hepatic blood flow) in rats, which translates into good oral bioavailability. Dogs exhibited high clearance, or about 95% of hepatic blood flow. In dogs, oral bioavailability can be as low as 16% due to low systemic exposure. While the low intrinsic clearance seen in rats and mice (mouse IVC 1.6 mL/min/g; CLb 8 mL/min/kg) is associated with lower in vivo blood clearance in these species, the high blood clearance in dogs is well correlated with the high intrinsic clearance observed in dog microsomes and hepatocytes. Owing to the low systemic exposure seen in dogs, minipigs were investigated as a possible second species for toxicological assessment. In these animals, I-BET151 demonstrated good bioavailability (65%) and low clearance (~32% hepatic blood flow)[1].
The preclinical tool compound I-BET151 has previously been shown to have antileukemia activity, and our data show that it is also active against myeloma in vivo[2]. A HLA-B27/β2m transgenic AS Lewis rat model was established and treated with 30 mg/kg I-BET151 for 5 weeks. Levels of receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), matrix metalloproteinase (MMP)3, and MMP9 were measured using ELISA in vivo and additionally detected with western blotting and polymerase chain reaction in vitro. The levels of RANKL, OPG, MMP3 and MMP9 were upregulated in AS serum, AS serum treated MG63 cells and HLA-B27/β2m transgenic AS rats. Conversely, levels of RANKL, OPG, MMP3 and MMP9 were significantly inhibited in cells or animals treated with I-BET151. Overall, the results of the present study demonstrated that BET inhibitor I-BET151 suppresses levels of RANKL, OPG, MMP3 and MMP9 in AS in vivo and in vitro. I-BET151 may exhibit the potential to be used as a therapeutic in the treatment of AS patients.[3] |
| Enzyme Assay |
Binding activity was assessed in BRD2, BRD3 and BRD4 fluorescence anisotropy (FP) assays as previously described [J. Med. Chem., 54 (2011), p. 3827]. Analogues of the isoxazoloquinolines competed with the FP ligand for binding to the bromodomains with sub-micromolar IC50’s, as shown in Table 1. A 1.8 Å resolution X-ray crystal structure of compound 1 was obtained by soaking into crystals of the BRD2 N-terminal bromodomain,6 revealing its binding mode (Fig. 1A)[1].
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| Cell Assay |
Cell Viability Assay[2]
Cell Types: H929 cells Tested Concentrations: 1 μM Incubation Duration: 72 hrs (hours) Experimental Results: Displays the majority of live cells resided in the G0 phase and commensurate with a dose- and time-dependent decrease in cell proliferation and abrogation of bromodeoxyuridine incorporation. Cell Proliferation Assay[2] Cell Types: H929 cells Tested Concentrations: 100 nM Incubation Duration: 72 hrs (hours) Experimental Results: Caused a significant dose- and time-dependent decrease in the proportion of myeloma cells in S/G2 phase. |
| Animal Protocol |
Animal/Disease Models: Mice (model of subcutaneous (sc) myeloma)[2]
Doses: 50 mg/kg Route of Administration: Ip; daily for 21 days Experimental Results: decreased rate of tumor size doubling than vehicle-treated mice. NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice were bred and maintained in-house at Imperial College in accordance with the 1986 Animal Scientific Procedures Act and under a United Kingdom Government Home Office–approved project license. In total, 5 × 106 KMS11 myeloma cells were injected subcutaneously into 9- to 12-week-old NSG mice. When tumors were ≥5 mm in maximum diameter, mice were randomized to receive once daily intraperitoneal injection of either I-BET151 30 mg/kg in 0.9% NaCl plus Kleptose hydroxypropyl betadex 10% (w/v) and DMSO 5% (v/v) pH 5.0 or vehicle solution for a maximum of 21 days[2]. AS animal model HLA-B27/β2 m transgenic AS Lewis rat model was constructed as previously described. A total of 20 AS rats were constructed and all animals (including normal Lewis rats, n=10) were housed in standard conditions under a 12-h light/dark cycle with free access to food and water. For I-BET151 treatment, 20 transgenic rats were intraperitoneally administrated with 30 mg/kg of I-BET151 (n=10; GlaxoSmithKline) and equal volume normal saline (n=10) once per day for 5 weeks. At the end of 5 weeks, all animals were anesthetized and 0.5 ml of blood samples were collected before sacrifice. [3] |
| References |
[1]. Identification of a novel series of BET family bromodomain inhibitors: Binding mode and profile of I-BET151 (GSK1210151A). Bioorg Med Chem Lett. 2012 Apr 15;22(8):2968-72.
[2]. Chaidos A, et al. Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762. Blood. 2014 Jan 30;123(5):697-705. [3]. I-BET151 inhibits expression of RANKL, OPG, MMP3 and MMP9 in ankylosing spondylitis in vivo and in vitro. Exp Ther Med . 2017 Nov;14(5):4602-4606. |
| Additional Infomation |
7-(3,5-dimethyl-4-isoxazolyl)-8-methoxy-1-[(1R)-1-(2-pyridinyl)ethyl]-3H-imidazo[4,5-c]quinolin-2-one is an imidazoquinoline.
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| Molecular Formula |
C23H21N5O3
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|---|---|---|
| Molecular Weight |
415.44
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| Exact Mass |
415.164
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| Elemental Analysis |
C, 66.49; H, 5.09; N, 16.86; O, 11.55
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| CAS # |
1300031-49-5
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| Related CAS # |
I-BET151 dihydrochloride;1883545-47-8
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| PubChem CID |
52912189
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| Appearance |
Typically exists as White to khaki solids at room temperature
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| Density |
1.3±0.1 g/cm3
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| Index of Refraction |
1.651
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| LogP |
2.28
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
31
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| Complexity |
665
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C[C@@H](N1C(C(C=C(OC)C(C2=C(C)ON=C2C)=C3)=C3N=C4)=C4NC1=O)C5=CC=CC=N5
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| InChi Key |
VUVUVNZRUGEAHB-CYBMUJFWSA-N
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| InChi Code |
InChI=1S/C23H21N5O3/c1-12-21(14(3)31-27-12)16-9-18-15(10-20(16)30-4)22-19(11-25-18)26-23(29)28(22)13(2)17-7-5-6-8-24-17/h5-11,13H,1-4H3,(H,26,29)/t13-/m1/s1
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| Chemical Name |
7-(3,5-dimethyl-1,2-oxazol-4-yl)-8-methoxy-1-[(1R)-1-pyridin-2-ylethyl]-3H-imidazo[4,5-c]quinolin-2-one
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.02 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 25.0 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: ≥ 2.5 mg/mL (6.02 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 25.0 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: ≥ 2.5 mg/mL (6.02 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 2.5 mg/mL (6.02 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 5: ≥ 2.5 mg/mL (6.02 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. 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. Solubility in Formulation 6: 0.5 mg/mL (1.20 mM) in 1% DMSO 99% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4071 mL | 12.0354 mL | 24.0709 mL | |
| 5 mM | 0.4814 mL | 2.4071 mL | 4.8142 mL | |
| 10 mM | 0.2407 mL | 1.2035 mL | 2.4071 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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