CEP-32496 hydrochlorideB-Raf/C-Raf inhibitor,highly potent CAS# 1227678-26-3 |
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Quality Control & MSDS
3D structure
Package In Stock
Number of papers citing our products
| Cas No. | 1227678-26-3 | SDF | Download SDF |
| PubChem ID | 56954675 | Appearance | Powder |
| Formula | C24H23ClF3N5O5 | M.Wt | 553.92 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | RXDX-105 hydrochloride; Agerafenib hydrochloride | ||
| Solubility | DMSO | ||
| Chemical Name | 1-[3-(6,7-dimethoxyquinazolin-4-yl)oxyphenyl]-3-[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]urea;hydrochloride | ||
| SMILES | CC(C)(C1=CC(=NO1)NC(=O)NC2=CC(=CC=C2)OC3=NC=NC4=CC(=C(C=C43)OC)OC)C(F)(F)F.Cl | ||
| Standard InChIKey | XCZIYUDQUDWQHI-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C24H22F3N5O5.ClH/c1-23(2,24(25,26)27)19-11-20(32-37-19)31-22(33)30-13-6-5-7-14(8-13)36-21-15-9-17(34-3)18(35-4)10-16(15)28-12-29-21;/h5-12H,1-4H3,(H2,30,31,32,33);1H | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | CEP-32496 hydrochloride is a highly potent inhibitor of wild-type BRAF, V600E mutant BRAF and c-Raf with Kd values of 14 nM, 36 nM and 39 nM, respectively. | |||||
| Targets | wild-type BRAF | V600E mutant BRAF | c-Raf | |||
| IC50 | 14 nM (Kd) | 36 nM (Kd) | 39 nM (Kd) | |||
Kinase Assay
[1]
KINOMEscan competition binding assays are performed. Kinases are produced displayed on T7 phage or by expression in HEK-293 cells and tagged with DNA. Binding reactions are performed at rt for 1 h, and the fraction of kinase not bound to test compound (e.g., CEP-32496) is determined by capture with an immobilized affinity ligand and quantitation by quantitative PCR. Each kinase is tested individually against each compound. Kd values are determined using eleven serial 3-fold dilutions and presented as mean values from experiments performed in duplicate. Variability between individual values is less than 2-fold[1].
Cell Assay
[1]
A375 cells are seeded at 10,000 cells per well in DMEM with 10% fetal calf serum and allowed to attach. The cells are washed with PBS and switched to DMEM with 0.5% of serum and incubated overnight. The test compounds (e.g., CEP-32496; 10 μM) are then added at various concentrations with a final DMSO concentration of 0.5% and incubated for 72 h. At the end of incubation, a Cell Titer Blue is added per instructions, and incubation is continued for 3 h. Remaining viable cells are quantified by measuring the strength of the fluorescence signal using SoftMax Pro (excitation at 560 nm and emission at 590 nm). IC50 values are derived using a 9-point curve and are presented as mean values from experiments performed in duplicate[1].
Animal Administration
[1]
Mice[1]
Six to eight week old athymic nu/nu nude mice (20-25 g) are inoculated subcutaneously with Colo-205 tumor cells (1×106/mouse) in the right flank. Upon reaching an average tumor volume of 150-200 mm3 (10-12 days post implantation), animals are randomized into treatment groups (n=10 mice/group). Each group is dosed orally for 14 days with either vehicle only (22% HPβCD) or with CEP-32496 at 10, 30, or 100 mg/kg twice daily (BID), and each dose of drug is given in a volume of 0.1 mL per 20 g of body weight, adjusted for the body weight of the animal. Tumor volumes are measured three times weekly using vernier calipers, and volumes are calculated[1].
References:
[1]. Rowbottom MW, et al. Identification of 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea hydrochloride (CEP-32496), a highly potent and orally efficacious inhibitor of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) V600E.
CEP-32496 hydrochloride Dilution Calculator
CEP-32496 hydrochloride Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 1.8053 mL | 9.0266 mL | 18.0531 mL | 36.1063 mL | 45.1329 mL |
| 5 mM | 0.3611 mL | 1.8053 mL | 3.6106 mL | 7.2213 mL | 9.0266 mL |
| 10 mM | 0.1805 mL | 0.9027 mL | 1.8053 mL | 3.6106 mL | 4.5133 mL |
| 50 mM | 0.0361 mL | 0.1805 mL | 0.3611 mL | 0.7221 mL | 0.9027 mL |
| 100 mM | 0.0181 mL | 0.0903 mL | 0.1805 mL | 0.3611 mL | 0.4513 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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CEP-32496 is a selective inhibitor of BRAFV600E with IC50 value of 669 nM [1].
BRAF is a member of Raf kinase family and plays an important role in sending signals (directing cell growth) inside cells. BRAF involves in regulating MAP kinase/ERKs signaling pathway and mutant BRAFV600E activates MAPK pathway, it has been shown that BRAF mutant BRAFV600E is correlated with several human cancers [2].
CEP-32496 is a potent BRAFV600E inhibitor and has a different selectivity with the reported BRAFV600E inhibitor RG7204. Using Ambit Kinomescan Assay, it was shown that CEP-32496 potently binding to RAF family with Kd value ranged from 14 to 39 nmol/L. When tested with a panel of BRAF mutant (A375, SK-MEL-28, Colo-679, HT-144, and Colon-205) cell lines, CEP-32496 showed a selective cytotoxicity profile against tumor cell lines with V600E mutant while had no effect on wild type cell lines (HCT116, Hs578T, LNCaP, DU145, PC-3) [1]. CEP-32496 treatment exhibited high cytotoxicity against human tumor cell lines with expression of BRAFV600E while had little effect on wild type BRAF expressed cell lines [2].
In nude mice model with Colo-205 tumor cells subcutaneous xenograft, oral administration of CEP-32496 significantly inhibited pMEK normalization, induced tumor stasis (40%) while control group did not have this phenomenon in a dose of 30 mg/kg [1].
CEP-32496 also inhibits MEK phosphorylation with IC 50 value of 60 nM [1].
References:
[1].James, J., et al., CEP-32496: a novel orally active BRAF(V600E) inhibitor with selective cellular and in vivo antitumor activity. Mol Cancer Ther, 2012. 11(4): p. 930-41.
[2].Rowbottom, M.W., et al., Identification of 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropa n-2-yl)isoxazol-3-yl)urea hydrochloride (CEP-32496), a highly potent and orally efficacious inhibitor of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) V600E. J Med Chem, 2012. 55(3): p. 1082-105.
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Identification of 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropa n-2-yl)isoxazol-3-yl)urea hydrochloride (CEP-32496), a highly potent and orally efficacious inhibitor of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) V600E.[Pubmed:22168626]
J Med Chem. 2012 Feb 9;55(3):1082-105.
The Ras/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway plays a central role in the regulation of cell growth, differentiation, and survival. Expression of mutant BRAF(V600E) results in constitutive activation of the MAPK pathway, which can lead to uncontrolled cellular growth. Herein, we describe an SAR optimization campaign around a series of quinazoline derived BRAF(V600E) inhibitors. In particular, the bioisosteric replacement of a metabolically sensitive tert-butyl group with fluorinated alkyl moieties is described. This effort led directly to the identification of a clinical candidate, compound 40 (CEP-32496). Compound 40 exhibits high potency against several BRAF(V600E)-dependent cell lines and selective cytotoxicity for tumor cell lines expressing mutant BRAF(V600E) versus those containing wild-type BRAF. Compound 40 also exhibits an excellent PK profile across multiple preclinical species. In addition, significant oral efficacy was observed in a 14-day BRAF(V600E)-dependent human Colo-205 tumor xenograft mouse model, upon dosing at 30 and 100 mg/kg BID.
