Regorafenib (BAY73-4506)

Alias: BAY-734506; BAY734506; BAY 734506; Regorafenib. Brand name: Stivarga

Cat No.:V0048 Purity: ≥98%

COA Product Data Instructions for use SDS

Regorafenib (also known as BAY 73-4506; BAY-73-4506) is a potent andorally bioavailable multi-kinase inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFRβ, Kit, RET and Raf-1 with IC50 values of 13 nM/4.2 nM/46 nM, 22 nM, 7 nM, 1.5 nM and 2.5 nM in cell-free assays, respectively.

Regorafenib (BAY73-4506) Chemical Structure CAS No.: 755037-03-7
Product category: c-RET

This product is for research use only, not for human use. We do not sell to patients.

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Other Forms of Regorafenib (BAY73-4506):

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Top Publications Citing lnvivochem Products

Nature 2021, 597(7874):119-125.

Cell 2020,183:1202-1218.e25.

Science Adv 2022: 8, eabm9427.

Nature 597, 119–125 (2021)

Cell Stem Cell 2020,26(6):845-861.e12.

Science Trans Med 2023,15(701):eadd7872.

STTT 2023,8(1):91.

Cell Reports 2023,42(4):112313

Science Trans Med 2023, 15: eadd7872.

Cancer Cell 2021,39(4):529-547.e7.

Cancer Discov 2022,12(4):1106-1127.

Immunity 2023,56(3):620-634.e11.

J Am Chem Soc 2022,144:21831-21836.

Cell 2020,183:1202-1218.e25.

Science Adv 2022:8,eabm9427.

Nature 2021,597(7874):119-125.

Cell 2020,183:1202-1218.e25.

PNAS Nexus 2022,1(3):pgac063.

ACS Nano 2023,17(10):9110-9125.

Biomaterial 2023 Sep16:302:122333.

Purity & Quality Control Documentation

Current batch：

Purity: ≥98%

COA

MSDS

NMR

Instructions

Product Description
Bioactivity & Protocols
Physicochemical Properties
Solubility Data
Calculators
Clinical Trial Information
Biological Data

Product Description

Regorafenib (also known as BAY 73-4506; BAY-73-4506) is a potent and orally bioavailable multi-kinase inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFRβ, Kit, RET and Raf-1 with IC50 values of 13 nM/4.2 nM/46 nM, 22 nM, 7 nM, 1.5 nM and 2.5 nM in cell-free assays, respectively. It has antitumor properties and was given FDA approval to treat liver cancer.

Biological Activity I Assay Protocols (From Reference)

Targets	Raf-1 (IC50 = 2.5 nM); Tie2 (IC50 = 311 ± 46 nM); VEGFR2 (IC50 = 4.2 nM); VEGFR1 (IC50 = 13 nM); VEGFR2 (IC50 = 4.2 nM); BRafV600E (IC50 = 19 nM); PDGFRβ (IC50 = 22 nM); Braf (IC50 = 28 nM); VEGFR3 (IC50 = 46 nM)
ln Vitro	Regorafenib (0-10 μM, 96 h) exhibits anti-proliferation activity in GIST 882, Thyroid TT, MDA-MB-231, HepG2, A375, and SW620 cells[1]. Regorafenib (0–3000 nM, 30 min) inhibits FGFR and pERK1/2 as well as the autophosphorylation of VEGFR2, TIE2, and PDGFR-β. Regorafenib has an IC50 of 5 μM and inhibits Hep3B cell growth in a concentration-dependent manner. Regorafenib then elevates phospho-c-Jun levels in Hep3B cells, a JNK target, but not total c-Jun levels[3].
ln Vivo	Regorafenib (10 mg/kg, Orally, once or twice daily for 4 days) inhibits tumor growth and tumor vasculature in a rat GS9L glioblastoma model[1]. Regorafenib (0-100 mg/kg, Orally, qd × 9) exhibits antitumorigenic and antiangiogenic effects in the Colo-205, MDA-MB-231 and 786-O model[1].
Enzyme Assay	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. At a constant 1 μM Regorafenib concentration, the initial in vitro kinase inhibition profiling is carried out. Select responding kinases, such as VEGFR1 and RET, are used to calculate the 50% inhibitory concentration (IC50) values. Using a recombinant fusion protein of glutathione-S-transferase, the intracellular domain of TIE2, and the peptide biotin-Ahx-EPKDDAYPLYSDFG as substrate, the homogeneous time-resolved fluorescence (HTRF) assay is used to measure TIE2 kinase inhibition.
Cell Assay	For proliferation tests, GIST 882 and TT cells are grown in RPMI medium with L-glutamine, while MDA-MB-231, HepG2, and A375 cells are grown in DMEM that is always supplemented with 10% high-fat b-casein sulfate. Trypsinized cells are plated at 5×104 cells per well in 96-well plates with complete media containing 10% FBS, and grown overnight at 37 °C. The incubation is continued for another 96 hours with the addition of vehicle or Regorafenib, serially diluted in complete growth media to final concentrations between 10 μM and 5 nM, and 0.2% DMSO. You can measure cell proliferation.
Animal Protocol	Female athymic NCr nu/nu mice with Colo-205, MDA-MB-231 or 786-O 3 mg/kg, 10 mg/kg, 30 mg/kg, 100 mg/kg Orally
References	[1]. Int J Cancer . 2011 Jul 1;129(1):245-55. [2]. Ther Adv Med Oncol . 2010 Jan;2(1):39-49. [3]. J Cell Physiol . 2013 Feb;228(2):292-7.

These protocols are for reference only. InvivoChem does not independently validate these methods.

Physicochemical Properties

Molecular Formula	C21H15CLF4N4O3
Molecular Weight	482.82
Exact Mass	482.07688
Elemental Analysis	C, 52.24; H, 3.13; Cl, 7.34; F, 15.74; N, 11.60; O, 9.94
CAS #	755037-03-7
Related CAS #	Regorafenib monohydrate;1019206-88-2;Regorafenib-d3;1255386-16-3;Regorafenib Hydrochloride;835621-07-3;Regorafenib mesylate;835621-08-4;Regorafenib-13C,d3
Appearance	Off-white to light pink solid powder
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
InChi Key	FNHKPVJBJVTLMP-UHFFFAOYSA-N
InChi Code	InChI=1S/C21H15ClF4N4O3/c1-27-19(31)18-10-13(6-7-28-18)33-12-3-5-17(16(23)9-12)30-20(32)29-11-2-4-15(22)14(8-11)21(24,25)26/h2-10H,1H3,(H,27,31)(H2,29,30,32)
Chemical Name	4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide
Synonyms	BAY-734506; BAY734506; BAY 734506; Regorafenib. Brand name: Stivarga
HS Tariff Code	2934.99.9001
Storage	Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility Data

Solubility (In Vitro)

DMSO: ~97 mg/mL (~200.9 mM)

Water: <1 mg/mL (slightly soluble or insoluble)

Ethanol: N/A

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 7.5 mg/mL (15.53 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 75.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

Solubility in Formulation 2: 2.75 mg/mL (5.70 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.18 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 4: 30% PEG400+0.5% Tween80+5% Propylene glycol : 30mg/mL

(Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.0712 mL	10.3558 mL	20.7117 mL
	5 mM	0.4142 mL	2.0712 mL	4.1423 mL
	10 mM	0.2071 mL	1.0356 mL	2.0712 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.

Calculator

Mass

Concentration

Volume

Molecular Weight*

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Molarity Calculator allows you to calculate the mass, volume, and/or concentration required for a solution, as detailed below:

Calculate the Mass of a compound required to prepare a solution of known volume and concentration
Calculate the Volume of solution required to dissolve a compound of known mass to a desired concentration
Calculate the Concentration of a solution resulting from a known mass of compound in a specific volume

See Example

An example of molarity calculation using the molarity calculator is shown below:
What is the mass of compound required to make a 10 mM stock solution in 5 ml of DMSO given that the molecular weight of the compound is 350.26 g/mol?

Enter 350.26 in the Molecular Weight (MW) box
Enter 10 in the Concentration box and choose the correct unit (mM)
Enter 5 in the Volume box and choose the correct unit (mL)
Click the “Calculate” button
The answer of 17.513 mg appears in the Mass box. In a similar way, you may calculate the volume and concentration.

Concentration (Start)

Volume (Start)

Concentration (End)

Volume (End)

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Dilution Calculator allows you to calculate how to dilute a stock solution of known concentrations. For example, you may Enter C1, C2 & V2 to calculate V1, as detailed below:

What volume of a given 10 mM stock solution is required to make 25 ml of a 25 μM solution?
Using the equation C1V1 = C2V2, where C1=10 mM, C2=25 μM, V2=25 ml and V1 is the unknown:

Enter 10 into the Concentration (Start) box and choose the correct unit (mM)
Enter 25 into the Concentration (End) box and select the correct unit (mM)
Enter 25 into the Volume (End) box and choose the correct unit (mL)
Click the “Calculate” button
The answer of 62.5 μL (0.1 ml) appears in the Volume (Start) box

Molecular formula

Total molecular weight

g/mol

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Molecular Weight Calculator allows you to calculate the molar mass and elemental composition of a compound, as detailed below:

Note: Chemical formula is case sensitive: C12H18N3O4 c12h18n3o4
Instructions to calculate molar mass (molecular weight) of a chemical compound:

To calculate molar mass of a chemical compound, please enter the chemical/molecular formula and click the “Calculate’ button.

Definitions of molecular mass, molecular weight, molar mass and molar weight:

Molecular mass (or molecular weight) is the mass of one molecule of a substance and is expressed in the unified atomic mass units (u). (1 u is equal to 1/12 the mass of one atom of carbon-12)
Molar mass (molar weight) is the mass of one mole of a substance and is expressed in g/mol.

Volume (to add to vial)

Mass (in vial)

Desired Reconstitution Concentration

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Reconstitution Calculator allows you to calculate the volume of solvent required to reconstitute your vial.

Enter the mass of the reagent and the desired reconstitution concentration as well as the correct units
Click the “Calculate” button
The answer appears in the Volume (to add to vial) box

In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)

Dosage mg/kg

Average weight of animals g

Dosing volume per animal μL

Number of animals

Step 2: Enter in vivo formulation (This is only a calculator, not the exact formulation for a specific product. Please contact us first if there is no in vivo formulation in the solubility section.)

% DMSO

% Tween 80

% ddH₂O

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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.

Note： (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.

Clinical Trial Information

NCT Number	Recruitment	interventions	Conditions	Sponsor/Collaborators	Start Date	Phases
NCT03042689	Active Recruiting	Drug: Regorafenib	Acute Myeloid Leukemia	Massachusetts General Hospital	April 17, 2017	Phase 1
NCT03712943	Active Recruiting	Drug: Regorafenib Drug: Nivolumab	Colon Cancer Colorectal Cancer Metastatic Colorectal Cancer	H. Lee Moffitt Cancer Center and Research Institute	October 23, 2018	Phase 1
NCT04051606	Active Recruiting	Drug: Regorafenib	Recurrent Glioblastoma	Case Comprehensive Cancer Center	July 31, 2019	Phase 2
NCT04170556	Active Recruiting	Drug: Regorafenib Drug: Nivolumab	Hepatocellular Carcinoma	Fundacion Clinic per a la Recerca Biomédica	March 16, 2020	Phase 1 Phase 2
NCT02098538	Active Recruiting	Drug: Regorafenib	Adenoid Cystic Carcinoma	Memorial Sloan Kettering Cancer Center	March 2014	Phase 2

Biological Data

Regorafenib inhibits growth-factor-stimulated VEGFR2 and VEGFR3 autophosphorylation in human umbilical vascular endothelialcells (HuVECs) and intracellular signaling and migration in lymphatic endothelial cells (LECs).

Regorafenib inhibits key kinase targets in cells expressing VEGFR2, TIE2, PDGFR‐β, or FGFR.Int J Cancer.2011 Jul 1;129(1):245-55.
Regorafenib inhibits tumor vasculature and tumor growth in a rat GS9L glioblastoma model: time‐course analysis by DCE‐MRI.Int J Cancer.2011 Jul 1;129(1):245-55.
Regorafenib significantly reduces tumor MVA in the Colo‐205 CRC xenograft model.Int J Cancer.2011 Jul 1;129(1):245-55.
Regorafenib exhibits antitumorigenic and antiangiogenic effects in the MDA‐MB‐231 breast xenograft model.Int J Cancer.2011 Jul 1;129(1):245-55.
In vivoantitumor efficacy of regorafenib.Int J Cancer.2011 Jul 1;129(1):245-55.