CEP-32496 hydrochloride
(Synonyms: CEP 32496 hydrochloride;CEP32496 hydrochloride) 目录号 : GC17860
A potent inhibitor of B-Raf
Cas No.:1227678-26-3
Sample solution is provided at 25 µL, 10mM.
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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.
Cell experiment: | 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., Agerafenib (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 experiment: | 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 Agerafenib (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. | |
| Cas No. | 1227678-26-3 | SDF | |
| 别名 | CEP 32496 hydrochloride;CEP32496 hydrochloride | ||
| 化学名 | 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 | ||
| Canonical 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 | ||
| 分子式 | C24H23ClF3N5O5 | 分子量 | 553.92 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.8053 mL | 9.0266 mL | 18.0531 mL |
| 5 mM | 0.3611 mL | 1.8053 mL | 3.6106 mL |
| 10 mM | 0.1805 mL | 0.9027 mL | 1.8053 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
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