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Purity: ≥98%
CBL0137 HCl, the hydrochloride salt of CBL-0137 (formerly Curaxin 137 or CBL 0137), is an inhibitor of the histone chaperone, FACT (facilitates chromatin transcription complex). With EC50s of 0.37 μM and 0.47 μM in the cell-based p53 and NF-kB reporter assays, respectively, it also activates p53 and inhibits NF-kB. For glioblastoma and hematological malignancies, CBL0137 has begun clinical trials. In preclinical models of pancreatic cancer, CBL0137 kills cancer stem cells that are resistant to treatment and increases the effectiveness of gemcitabine. The chromatin remodeling complex FACT is inhibited by curaxins, which modulate a number of significant signaling pathways involved in the pathogenesis of pancreatic ductal adenocarcinoma (PDA). FACT is overexpressed in several different tumor types, with PDA having the highest rate of overexpression (59%).
| Targets |
p53 (IC50 = 0.37 μM); NF-κB (IC50 = 0.47 μM); FACT
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| ln Vitro |
CBL0137 is a potent inducer of apoptosis in pancreatic cancer cell lines and toxic to both pancreatic cancer stem cells and bulk tumor cells that are actively proliferating. Inhibiting cellular stress pathways controlled by NF-B and HSF-1 while simultaneously activating p53 is possible with CBL0137 and related molecules[2]. CBL0137 binds DNA without introducing any kind of chemical alterations, making it non-genotoxic. The Facilitates Chromatin Transcription (FACT) complex, a chromatin remodeling complex involved in transcription, replication, and DNA repair, is functionally inactivated as a result of CBL0137 binding to DNA. FACT is lost from the nucleoplasm and becomes trapped in chromatin in CBL0137-treated cells, which inhibits FACT-dependent transcription, including NF-kB-mediated transcription. Additionally, chromatin trapping of FACT results in the phosphorylation and activation of p53 in a casein kinase 2 (CK2)-dependent manner[3].
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| ln Vivo |
In mice, CBL0137 is effective against several Pancreatic ductal adenocarcinoma (PDA) models, including orthotopic gemcitabine resistant PANC-1 model and patient derived xenografts, in which CBL0137 anti-tumor effect correlated with overexpression of FACT[1]. According to its proposed mechanism of action, CBL0137 targets glioblastoma (GBM), penetrates the blood-brain barrier, and is effective in both TMZ-responsive and -resistant orthotopic models. The ability of this medication to cross the blood-brain barrier, especially when given intravenously, is encouraging for its potential to treat CNS tumors. In orthotopic models, intravenously administered drugs have higher bioavailability than those administered orally because they accumulate more in tumor tissue. The normal buildup of CBL0137 in brain tissue does not result in detectable neurotoxicity[3].
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| Enzyme Assay |
CBL0137 hydrochloride is applied to MiaPaca2 and BxPC-3 cells for 4 or 24 hours. Protease and phosphatase inhibitors are present in 1× Cell Culture Lysis Reagent, which is used to harvest cells. Lysates 5 to 20 μg are transferred to PVDF membranes after being separated on SDS-PAGE gels. Antibodies that target the proteins SSRP1, SPT16, RRM1 and RRM2 are used to probe blots. The loading control is GAPDH. ECL kit is used to visualize proteins[1].
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| Cell Assay |
Cells are resuspended in serum-free Dulbecco's Modified Eagle Medium (DMEM) and exposed to varying concentrations of CBL0137 hydrochloride for 1h. Then, 105 cells from each treatment condition are plated in 3 wells of a 6-well plate in 2 mL of serum-free DMEM/F12 medium supplemented with 0.4% BSA, 0.2×B27, 10 ng/mL recombinant EGF, and containing 0.25% agarose. In three wells of a 6-well plate with regular FBS-containing medium, 103 cells from each treatment condition are plated. Seven to fifteen days after plating, colonies are counted under an inverted microscope.
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| Animal Protocol |
Ketamine/xylazine is used to create a deep anesthesia in 10-week-old female athymic nude mice (n = 8 per treatment group). Each mouse has its pancreas tail inoculated with 2 106 PANC-1 cells via laparotomy. When the tumor was detected by ultrasound two weeks after the vaccination, treatment started. There are the following routines: 1) Vehicles, gavage of sterile water and 100 mg/kg captisol 2) 100 mg/mL captisol diluted with 50 to 90 mg/kg CBL0137 hydrochloride and given intravenously once a week via the tail vein; 3) 10 to 20 mg/kg CBL0137 hydrochloride given orally five days on and two days off. To measure tumors, digital calipers are used. The equation LW2/2 is used to determine the tumor volume, where L is the longest dimension and W is the dimension that is perpendicular to W. Mice are monitored for at least 90 days after the start of treatment or until at least one tumor per mouse reached 1000 mm3, whichever occurs first.
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| References |
| Molecular Formula |
C21H24N2O2-HCL
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| Molecular Weight |
372.89
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| Elemental Analysis |
C, 67.64; H, 6.76; Cl, 9.51; N, 7.51; O, 8.58
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| CAS # |
1197397-89-9
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| Related CAS # |
CBL0137;1197996-80-7
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| Appearance |
Solid powder
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| SMILES |
CC(C)NCCN1C2=C(C=C(C=C2)C(=O)C)C3=C1C=CC(=C3)C(=O)C.Cl
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| InChi Key |
IXRKBBVMDMKAEB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H24N2O2.ClH/c1-13(2)22-9-10-23-20-7-5-16(14(3)24)11-18(20)19-12-17(15(4)25)6-8-21(19)23;/h5-8,11-13,22H,9-10H2,1-4H3;1H
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| Chemical Name |
1-[6-acetyl-9-[2-(propan-2-ylamino)ethyl]carbazol-3-yl]ethanone;hydrochloride
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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 (6.70 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 (6.70 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: 5%DMSO+40%PEG300+5%Tween80+50%ddH2O: 0.75mg/ml |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6818 mL | 13.4088 mL | 26.8176 mL | |
| 5 mM | 0.5364 mL | 2.6818 mL | 5.3635 mL | |
| 10 mM | 0.2682 mL | 1.3409 mL | 2.6818 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.
CBL0137 and gemcitabine toxicity to pancreatic ductal adenocarcinoma cell lines.Oncotarget.2014 Nov 30;5(22):11038-53. |
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Effect of CBL0137 and gemcitabine on orthotopic PANC1 pancreatic tumor growth in nude mice.Oncotarget.2014 Nov 30;5(22):11038-53. |
Morphology and expression of FACT subunits (SSRP1, SPT16) and proliferation marker Ki67 in PDX samples of pancreatic ductal adenocarcinoma (PDA) used in the study.Oncotarget.2014 Nov 30;5(22):11038-53. |
Effect of CBL0137 and gemcitabine on patient derived PDA xenograft models.Oncotarget.2014 Nov 30;5(22):11038-53. |
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CBL0137 inhibit gemcitabine induced transcriptional responses.Oncotarget.2014 Nov 30;5(22):11038-53. |
CBL0137 is toxic for cancer stem cells (CSC).Oncotarget.2014 Nov 30;5(22):11038-53. |
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