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Purity: ≥98%
RGB-286638 2HCl, the dihydrochloride salt of RGB-286638, is a multi-targeted cyclin-dependent kinase (CDK) inhibitor. It has IC50 values of 1, 2, 3, 4, 5, and 5 nM for cyclin T1-CDK9, B1-CDK1, E-CDK2, D1-CDK4, E-CDK3, and p35-CDK5 kinase activity inhibition; IC50 values of 3, 5, 50, and 54 nM for GSK-3β, TAK1, Jak2, and MEK1 kinase activity inhibition are also observed. RGB-286638 inhibits transcriptional CDKs, which in turn initiates P53-dependent and -independent anti-multiple myeloma (MM) activity. When MM tumor growth was inhibited and in vivo survival was extended, GB-286638 treatment led to MM cytotoxicity in vitro. Both wt-p53 and mutant-p53 cells showed caspase-dependent apoptosis, which was closely linked to transcription inhibition and RNA polymerase II phosphorylation downregulation.
| Targets |
T1-CDK9 (IC50 = 1 nM); cyclin B1-CDK1 (IC50 = 2 nM); cyclin E-CDK2 (IC50 = 3 nM); cyclin D1-CDK4 (IC50 = 4 nM); cyclin E-CDK3 (IC50 = 5 nM); p35-CDK5 (IC50 = 5 nM); cyclin H-CDK7 (IC50 = 44 nM); cyclin D3-CDK6 (IC50 = 55 nM); GSK-3β (IC50 = 3 nM); JAK2 (IC50 = 50 nM); MEK1 (IC50 = 54 nM); Fms (IC50 = 1 nM); TAK1 (IC50 = 5 nM); JNK1a1 (IC50 = 17 nM); JNK1a2 (IC50 = 40 nM); C-src (IC50 = 25 nM); AMPK (IC50 = 41 nM)
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| ln Vitro |
RGB-286638 is a CDK inhibitor (CDKI) derived from indenopyrazole that exhibits Ki-nanomolar activity against transcriptional CDKs. AMPK, Jak2, MEK1, TAK1, GSK-3β, and other tyrosine and serine/threonine non-CDK enzymes are all inhibited by RGB-286638. By using the MTT assay to measure viability at 24 and 48 hours, the effects of RGB-286638 (12.5-100nM) treatment are examined on the growth of human p53-wt (MM.1S, MM.1R, and H929) and p53-mutant (U266, OPM1, and RPMI) MM cells. After 48 hours, the half-maximally effective concentrations (EC50) vary from 20 to 70 nM. Following 50nM treatment, dose-dependent growth differences between p53-wt and -mutant cells are seen, with p53-wt MM.1S, MM.1R, and H929 showing a slight increase in sensitivity to RGB-286638 treatment at 48 hours[1].
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| ln Vivo |
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| Enzyme Assay |
The Nuclear Extraction Kit is used to isolate nuclear proteins from MM.1S cells that have been exposed to 50nM RGB-286638 for 1, 4, and 8 hours. A specific double-stranded DNA sequence containing the p53 response element is coated on 96-well plates, and nuclear protein aliquots are added for an overnight incubation. By adding a particular primary antibody that targets p53, p53 in the nuclear extract can be identified. A sensitive colorimetric readout at 450 nm is achieved by adding a secondary antibody conjugated to HRP. Triple-checking is done on every experiment[1].
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| Cell Assay |
Colorimetric assays are used to measure the efficacy of drugs at progressively higher RGB-286638 concentrations (0-100nM). 100 μL of isopropanol containing 0.04 HCl is added to each well after 10μL of 5 mg/mL MTT is pulsed into each well of p53-expressing wild-type (MM.1S, MM.1R, H929) or mutant (U266, OPM1, RPMI) cells from 24- or 48-hour cultures. The cells are then incubated at 37°C for 4 hours. Using a spectrophotometer, absorbance measurements are made at 570 nm wavelength (corrected using readings at 630 nm). Three duplicates of each experiment are run[1].
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| References |
| Molecular Formula |
C29H37CL2N7O4
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|---|---|
| Molecular Weight |
618.6
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| Exact Mass |
617.2284081
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| CAS # |
784210-87-3
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| Related CAS # |
RGB-286638 free base;784210-88-4
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| Appearance |
solid
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| SMILES |
COCCN1CCN(CC1)CC2=CC=C(C=C2)C3=NNC4=C3C(=O)C5=C4C=CC=C5NC(=O)NN6CCOCC6.Cl.Cl
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| InChi Key |
WJVMGQMXUBAAPL-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C29H35N7O4.2ClH/c1-39-16-13-34-9-11-35(12-10-34)19-20-5-7-21(8-6-20)26-25-27(32-31-26)22-3-2-4-23(24(22)28(25)37)30-29(38)33-36-14-17-40-18-15-36;;/h2-8H,9-19H2,1H3,(H,31,32)(H2,30,33,38);2*1H
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| Chemical Name |
1-[3-[4-[[4-(2-methoxyethyl)piperazin-1-yl]methyl]phenyl]-4-oxo-1H-indeno[1,2-c]pyrazol-5-yl]-3-morpholin-4-ylurea;dihydrochloride
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| Synonyms |
RGB-286638 2HCl; RGB 286638 2HCl; RGB2866382HCl
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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: ≥ 7.5 mg/mL (12.13 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 75.0 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: ≥ 7.5 mg/mL (12.13 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 75.0 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6166 mL | 8.0828 mL | 16.1655 mL | |
| 5 mM | 0.3233 mL | 1.6166 mL | 3.2331 mL | |
| 10 mM | 0.1617 mL | 0.8083 mL | 1.6166 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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RGB-286638 Demonstrated Potent Activity Against Transcriptional CDKs in MM Cell Lines and Inhibited Myeloma Cell Growthin Vitro.Leukemia.2013 Dec;27(12):2366-75. |
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RGB-286638 Inhibited Transcription.Leukemia.2013 Dec;27(12):2366-75. |
RGB-286638 Effects on miRNA Expression.Leukemia.2013 Dec;27(12):2366-75. |
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