Regorafenib hydrochloride
(Synonyms: 瑞戈非尼盐酸盐; BAY 73-4506 hydrochloride) 目录号 : GC14606A multi-kinase inhibitor
Cas No.:835621-07-3
Sample solution is provided at 25 µL, 10mM.
Regorafenib Hydrochloride is a multi-target inhibitor for VEGFR1/2/3, PDGFRβ, Kit, RET and Raf-1 with IC50s of 13/4.2/46, 22, 7, 1.5 and 2.5 nM, respectively.
Regorafenib potently inhibits VEGFR2 autophosphorylation in NIH-3T3/VEGFR2 cells with an IC50 of 3 nM. In HAoSMCs, regorafenib inhibits PDGFR-β autophosphorylation after stimulation with PDGF-BB, with an IC50 of 90 nM. Regorafenib inhibits the proliferation of VEGF165-stimulated HUVECs, with an IC50 of 3 nM[1]. Regorafenib causes a concentration-dependent decrease in Hep3B cell growth, having an IC50 of 5 μM. Regorafenib subsequently increases the levels of phospho-c-Jun, a JNK target, but not total c-Jun in Hep3B cells[3].
Regorafenib effectively inhibits growth of the Colo-205 xenografts in the dose range of 10-100 mg/kg reaching a TGI of 75% at day 14 at the 10 mg/kg dose. In the MDA-MB-231 model, regorafenib is highly efficacious at a dose as low as 3 mg/kg, resulting in a significant TGI of 81%, which increases to 93% at doses of 10 and 30 mg/kg, where tumor stasis is reached[1].
References:
[1]. Wilhelm SM, et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer, 2011, 129(1), 245-255.
[2]. Heng DY, et al. Targeted therapy for metastatic renal cell carcinoma: current treatment and future directions. Ther Adv Med Oncol, 2010, 2(1), 39-49.
[3]. Carr BI, et al. Fluoro-Sorafenib (Regorafenib) effects on hepatoma cells: growth inhibition, quiescence, and recovery. J Cell Physiol, 2013, 228(2), 292-297.
Kinase experiment: | Initial in vitro kinase inhibition profiling is performed at Millipore Corporation at a fixed 1 μM compound concentration under Millipore standard conditions [10 μM adenosine-5′-triphosphate (ATP) concentration]. Inhibitory concentration of 50% (IC50) values are determined from selected responding kinases,e.g., VEGFR1 and RET. TIE2 kinase inhibition is measured with a homogeneous time-resolved fluorescence (HTRF) assay using a recombinant fusion protein of glutathione-S-transferase, the intracellular domain of TIE2 and the peptide biotin-Ahx-EPKDDAYPLYSDFG as substrate. |
Cell experiment: | For proliferation assays, GIST 882 and TT cells are grown in RPMI medium containing L-glutamine, and MDA-MB-231, HepG2 and A375 cells in DMEM always containing 10% hiFBS. Cells are trypsinized, plated at 5×104 cells/well in 96-well plates in complete media containing 10% FBS and grown overnight at 37°C. The next day, vehicle or regorafenib serially diluted in complete growth media to between 10 μM and 5 nM final concentrations, and 0.2% DMSO, is added and incubation is continued for 96 hr. Cell proliferation is quantified using CellTitre-GloTM. |
Animal experiment: | Female athymic NCr nu/nu mice, kept in accordance with Federal guidelines, are subcutaneously inoculated with 5×106 Colo-205 or MDA-MB-231 cells or implanted with 1 mm3 786-O tumor fragments. When tumors reach a volume of 100 mm3, regorafenib or vehicle control is administered orally qd×21 in the 786-O model, and qd×9 in the Colo-205 and MDA-MB-231 models, respectively, at doses of 100, 30, 10, and 3 mg/kg. Paclitaxel is administered intravenously at 10 mg/kg in ethanol/Cremophor EL®/saline (12.5%/12.5%/75%) every 2 days×5. Tumor size (volume) is estimated twice weekly (l×w2)/2, and the percentage of tumor growth inhibition (TGI) is obtained from terminal tumor weights (1-T/C×100). Mice are weighed every other day starting from the first day of treatment. The general health status of the mice is monitored daily. |
References: [1]. Wilhelm SM, et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer, 2011, 129(1), 245-255. |
Cas No. | 835621-07-3 | SDF | |
别名 | 瑞戈非尼盐酸盐; BAY 73-4506 hydrochloride | ||
化学名 | 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide hydrochloride | ||
Canonical SMILES | CNC(=O)C1=NC=CC(=C1)OC2=CC(=C(C=C2)NC(=O)NC3=CC(=C(C=C3)Cl)C(F)(F)F)F.Cl | ||
分子式 | C21H16Cl2F4N4O3 | 分子量 | 519.28 |
溶解度 | ≥ 25.95 mg/mL in DMSO, ≥ 8.75 mg/mL in EtOH with ultrasonic and warming | 储存条件 | Store at -20°C |
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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 | |||
1 mg | 5 mg | 10 mg | |
1 mM | 1.9257 mL | 9.6287 mL | 19.2574 mL |
5 mM | 0.3851 mL | 1.9257 mL | 3.8515 mL |
10 mM | 0.1926 mL | 0.9629 mL | 1.9257 mL |
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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 | |||
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% DMSO % % Tween 80 % saline | ||||||||||
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工作液浓度: mg/ml;
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2.
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