Regorafenib (BAY 73-4506)

Regorafenib (BAY 73-4506) is a multi-target inhibitor for VEGFR1, VEGFR2, VEGFR3, PDGFRβ, Kit, RET and Raf-1 with IC50 of 13 nM/4.2 nM/46 nM, 22 nM, 7 nM, 1.5 nM and 2.5 nM, respectively.

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Regorafenib (BAY 73-4506) Chemical Structure

Regorafenib (BAY 73-4506) Chemical Structure
Molecular Weight: 482.82

Validation & Quality Control

Customer Reviews(2)

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Product Description

Biological Activity

Description Regorafenib (BAY 73-4506) is a multi-target inhibitor for VEGFR1, VEGFR2, VEGFR3, PDGFRβ, Kit, RET and Raf-1 with IC50 of 13 nM/4.2 nM/46 nM, 22 nM, 7 nM, 1.5 nM and 2.5 nM, respectively.
Targets RET [1] Raf-1 [1] VEGFR2 [1] Kit [1] VEGFR1 [1]

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IC50 1.5 nM 2.5 nM 4.2 nM 7 nM 13 nM
In vitro Regorafenib strongly prevents VEGFR2 autophosphorylation in NIH-3T3/VEGFR2 cells with IC50 of 3 nM. In HAoSMCs, regorafenib suppress PDGFR-β autophosphorylation after stimulation with PDGF-BB, with an IC50 of 90 nM. Regorafenib also inhibits FGFR signaling in MCF-7 breast cancer (BC) cells stimulated with FGF10. Regorafenib very potently inhibited the mutant receptors KITK642E and RETC634W, with IC50 of approximately 20 nM and 10 nM, respectively. Regorafenib inhibits the proliferation of VEGF165-stimulated HUVECs, with an IC50 of approximately 3 nM. Regorafenib prevents the proliferation of FGF2-stimulated HUVECs and of PDGF-BB-stimulated HAoSMCs with IC50 of 127 nM and 146 nM, respectively. [1] Regorafenib targets both tumor cell proliferation and tumor vasculature through inhibition of receptors of tyrosine kinases (VEGFR, KIT, RET, FGFR, and PDGFR) and serine/threonine kinases (Raf and p38MAPK). [2] Regorafenib suppresses growth of human Hep3B, PLC/PRF/5 and HepG2 cells in a concentration- and time-dependent manner. [3]
In vivo Regorafenib reveals potent dose-dependent TGI in various preclinical human xenograft models in mice, with tumor shrinkages in breast MDA-MB-231 and renal 786-O carcinoma models. Regorafenib prevents not only the growth of syngeneic primary 4T1 breast tumors growing orthotopically in the fat pad, but also suppresses the formation of tumor metastasis in the lung. [1]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

Kinase assays In vitro assays using recombinant VEGFR2 (murine aa785–aa1367), VEGFR3 (murine aa818–aa1363), PDGFRβ (aa561–aa1106), Raf-1 (aa305–aa648) and BRafV600E (aa409–aa765) kinase domains are performed. Initial in vitro kinase inhibition profiling is performed at a fixed 1 μM Regorafenib 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 Assay: [1]

Cell lines GIST 882 and TT cells
Concentrations 5 nM-10 μM
Incubation Time 96 hours
Method 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 hours. Cell proliferation is quantified.

Animal Study: [1]

Animal Models Female athymic NCr nu/nu mice with Colo-205, MDA-MB-231 or 786-O
Formulation PEG400/125 mM aqueous methanesulfonic acid (80/20) or polypropylene glycol/PEG400/Pluronic F68 (42.5/42.5/15 + 20% Aqua)
Dosages 3 mg/kg, 10 mg/kg, 30 mg/kg, 100 mg/kg
Administration Orally
Solubility 30% PEG400/0.5% Tween80/5% propylene glycol, , 30 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Conversion of different model animals based on BSA

SpeciesWeight (kg)Body Surface Area (m2)Km factor
Baboon120.620
Dog100.520
Monkey30.2412
Rabbit1.80.1512
Guinea pig0.40.058
Rat0.150.0256
Hamster0.080.025
Mouse0.020.0073
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

Value based on data from FDA Draft Guidelines: Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research. (2002) Estimating the safe starting dose in clinical trials for therapeutics in adult healthy volunteers, U.S. Food and Drug Administration, Rockville, Maryland, USA.

For example, to convert the dose of resveratrol used in a mouse (22.4 mg/kg) to a dose based on surface area for rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Wilhelm SM, et al. Int J Cancer, 2011, 129(1), 245-255.

[2] Heng DY, et al. Ther Adv Med Oncol, 2010, 2(1), 39-49.

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Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02175095 Not yet recruiting Colorectal Cancer Asan Medical Center July 2014 --
NCT02164240 Recruiting Gastrointestinal Stromal Tumor Dana-Farber Cancer Institute|Bayer|Pfizer July 2014 Phase 1
NCT02168777 Recruiting Neoplasms Bayer June 2014 Phase 1|Phase 2
NCT02116894 Not yet recruiting Colorectal Cancer Duke University|Herbert Hurwitz, MD|Pfizer June 2014 Phase 1
NCT02195011 Recruiting Colorectal Neoplasms SCRI Development Innovations, LLC|Sirtex Medical June 2014 Phase 2

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Chemical Information

Download Regorafenib (BAY 73-4506) SDF
Molecular Weight (MW) 482.82
Formula

C21H15ClF4N4O3

CAS No. 755037-03-7
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms Fluoro-Sorafenib
Solubility (25°C) * In vitro DMSO 97 mg/mL (200 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol, 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea

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Customer Reviews (2)


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Rating
Source J Clin Endocrinol Metab, 2013, 98(6):2502-12.. Regorafenib (BAY 73-4506) purchased from Selleck
Method MTT, Western blot
Cell Lines C-643, BC-PAP cells
Concentrations 0-10 uM
Incubation Time 48 h
Results Tipifarnib significantly enhanced the effect of increasing doses of gefitinib on cell viability in C-643 cells harboring the HRASG12A/Q61R mutation.

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Rating
Source Mol Pharmacol, 2013, 84(4):562-71.. Regorafenib (BAY 73-4506) purchased from Selleck
Method Tumor volume assay
Cell Lines Athymic female NCr-n/n mice
Concentrations 25 mg/kg
Incubation Time 3 d
Results Regorafenib significantly suppressed tumor growth.

Product Citations (2)

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