Regorafenib
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MedKoo CAT#: 202436

CAS#: 755037-03-7

Description: Regorafenib, also known as BAY 73-4506 ; is an orally bioavailable small molecule with potential antiangiogenic and antineoplastic activities. Regorafenib binds to and inhibits vascular endothelial growth factor receptors (VEGFRs) 2 and 3, and Ret, Kit, PDGFR and Raf kinases, which may result in the inhibition of tumor angiogenesis and tumor cell proliferation. Regorafenib demonstrated to increase the overall survival of patients with metastatic colorectal cancer and has been approved by the US FDA on September 27, 2012.


Chemical Structure

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Regorafenib
CAS# 755037-03-7

Theoretical Analysis

MedKoo Cat#: 202436
Name: Regorafenib
CAS#: 755037-03-7
Chemical Formula: C21H15ClF4N4O3
Exact Mass: 482.07688
Molecular Weight: 482.81541
Elemental Analysis: C, 52.24; H, 3.13; Cl, 7.34; F, 15.74; N, 11.60; O, 9.94

Price and Availability

Size Price Availability Quantity
200.0mg USD 150.0 Ready to ship
500.0mg USD 250.0 Ready to ship
1.0g USD 450.0 Ready to ship
2.0g USD 750.0 Ready to ship
5.0g USD 1250.0 Ready to ship
10.0g USD 1950.0 Ready to ship
20.0g USD 2650.0 Ready to ship
50.0g USD 3950.0 2 Weeks
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Synonym: BAY 734506; BAY734506; BAY-734506; Regorafenib. trade name: Stivarga.

IUPAC/Chemical Name: 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-N-methylpicolinamide

InChi Key: ZFLJHSQHILSNCM-UHFFFAOYSA-N

InChi Code: InChI=1S/C21H27N7O/c1-2-4-15(5-3-1)24-20-18-19(23-14-22-18)26-21(27-20)25-16-6-8-17(9-7-16)28-10-12-29-13-11-28/h6-9,14-15H,1-5,10-13H2,(H3,22,23,24,25,26,27)

SMILES Code: C12=NC(NC3=CC=C(N4CCOCC4)C=C3)=NC(NC5CCCCC5)=C1NC=N2

Appearance: Off-white to light pink solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Regorafenib (BAY 73-4506) is a multi-targeted receptor tyrosine kinase inhibitor with IC50s of 13/4.2/46, 22, 7, 1.5 and 2.5 nM for VEGFR1/2/3, PDGFRβ, Kit, RET and Raf-1, respectively.
In vitro activity: To identify the toxicity of regorafenib, this study performed MTT assay on CT26 and HT29 cells. Cell viability was decreased after regorafenib treatment as dose and time dependent manner (Fig. 1A-B). The IC50 of regorafenib in CT26 and HT29 is 22 μM and 20 μM at 24 h, respectively. Importantly, regorafenib may also suppress NF-κB activation as dose and time dependent manner (Fig. 1C-D). Furthermore, EGF induced NF-κB activity may be effectively suppressed by regorafenib as showed in Fig. 1E-F. EGF-induced EGFR phosphorylation was successfully diminished by regorafenib as illustrated in Fig. 1G. Erlotinib (EGFR inhibitor) obviously downregulated the phosphorylation of PKCδ, ERK, AKT and NF-κB (Fig. 1H-I). In Fig. 1J-L, the activation of downstream kinases (PKCδ, ERK, and AKT) and transcription factor (NF-κB) in EGFR signal transduction were all markedly decreased by regorafenib. In sum, regorafenib can effectively suppress EGFR signal transduction in CRC cells. Reference: Biomed Pharmacother. 2020 Aug;128:110319. https://pubmed.ncbi.nlm.nih.gov/32502841/
In vivo activity: Regorafenib 5 mg/kg/day, corresponding to about 50% of the recommended dosage for human based on clinical and preclinical pharmacokinetic data, exerted antitumor efficacy in both orthotopic and subcutaneous immune-competent liver cancer models (figure 1A). The difference in tumor growth measured at the end of the mouse study may reflect the combined effects of decreased cell proliferation (Ki67 staining), decreased tumor angiogenesis (CD31 staining), and increased tumor cell apoptosis (TUNEL assay) by regorafenib (figure 1B). Regorafenib increased CD4+ and CD8+ T cell infiltration into tumors, increased expression of genes related to T cell activation, antigen presentation, and macrophage activation, and suppressed genes related to angiogenesis (figure 1B, C,online supplemental table S2). While regorafenib induce cancer cell apoptosis dose dependently (online supplemental figure S1A, B), higher dosage of regorafenib inhibited T cell proliferation and activation in vitro (figure 1D, online supplemental figure S1C), suggesting that higher dosage of regorafenib may not be associated with better immune modulatory effects. Reference: J Immunother Cancer. 2021; 9(3): e001657. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986673/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMF 30.0 62.14
DMF:PBS (pH 7.2) (1:2) 0.3 0.62
Ethanol 14.0 30.0
DMSO 128.67 266.5

Preparing Stock Solutions

The following data is based on the product molecular weight 482.81541 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Liu YC, Tsai JJ, Weng YS, Hsu FT. Regorafenib suppresses epidermal growth factor receptor signaling-modulated progression of colorectal cancer. Biomed Pharmacother. 2020 Aug;128:110319. doi: 10.1016/j.biopha.2020.110319. Epub 2020 Jun 2. PMID: 32502841. 2. Subramonian D, Phanhthilath N, Rinehardt H, Flynn S, Huo Y, Zhang J, Messer K, Mo Q, Huang S, Lesperance J, Zage PE. Regorafenib is effective against neuroblastoma in vitro and in vivo and inhibits the RAS/MAPK, PI3K/Akt/mTOR and Fos/Jun pathways. Br J Cancer. 2020 Aug;123(4):568-579. doi: 10.1038/s41416-020-0905-8. Epub 2020 May 27. PMID: 32457362; PMCID: PMC7434894. 3. Ou DL, Chen CW, Hsu CL, Chung CH, Feng ZR, Lee BS, Cheng AL, Yang MH, Hsu C. Regorafenib enhances antitumor immunity via inhibition of p38 kinase/Creb1/Klf4 axis in tumor-associated macrophages. J Immunother Cancer. 2021 Mar;9(3):e001657. doi: 10.1136/jitc-2020-001657. PMID: 33753566; PMCID: PMC7986673. 4. Li X, Ma L, Huang K, Wei Y, Long S, Liu Q, Zhang D, Wu S, Wang W, Yang G, Zhou H, Yang C. Regorafenib-Attenuated, Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway. Int J Mol Sci. 2021 Feb 17;22(4):1985. doi: 10.3390/ijms22041985. PMID: 33671452; PMCID: PMC7922359.
In vitro protocol: 1. Liu YC, Tsai JJ, Weng YS, Hsu FT. Regorafenib suppresses epidermal growth factor receptor signaling-modulated progression of colorectal cancer. Biomed Pharmacother. 2020 Aug;128:110319. doi: 10.1016/j.biopha.2020.110319. Epub 2020 Jun 2. PMID: 32502841. 2. Subramonian D, Phanhthilath N, Rinehardt H, Flynn S, Huo Y, Zhang J, Messer K, Mo Q, Huang S, Lesperance J, Zage PE. Regorafenib is effective against neuroblastoma in vitro and in vivo and inhibits the RAS/MAPK, PI3K/Akt/mTOR and Fos/Jun pathways. Br J Cancer. 2020 Aug;123(4):568-579. doi: 10.1038/s41416-020-0905-8. Epub 2020 May 27. PMID: 32457362; PMCID: PMC7434894.
In vivo protocol: 1. Ou DL, Chen CW, Hsu CL, Chung CH, Feng ZR, Lee BS, Cheng AL, Yang MH, Hsu C. Regorafenib enhances antitumor immunity via inhibition of p38 kinase/Creb1/Klf4 axis in tumor-associated macrophages. J Immunother Cancer. 2021 Mar;9(3):e001657. doi: 10.1136/jitc-2020-001657. PMID: 33753566; PMCID: PMC7986673. 2. Li X, Ma L, Huang K, Wei Y, Long S, Liu Q, Zhang D, Wu S, Wang W, Yang G, Zhou H, Yang C. Regorafenib-Attenuated, Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway. Int J Mol Sci. 2021 Feb 17;22(4):1985. doi: 10.3390/ijms22041985. PMID: 33671452; PMCID: PMC7922359.

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1: Ravi S, Singal AK. Regorafenib: an evidence-based review of its potential in patients with advanced liver cancer. Core Evid. 2014 Jul 17;9:81-7. doi: 10.2147/CE.S48626. eCollection 2014. Review. PubMed PMID: 25114628; PubMed Central PMCID: PMC4109634.

2: Abdel-Rahman O, Fouad M. Risk of cardiovascular toxicities in patients with solid tumors treated with sunitinib, axitinib, cediranib or regorafenib: An updated systematic review and comparative meta-analysis. Crit Rev Oncol Hematol. 2014 Jul 1. pii: S1040-8428(14)00114-0. doi: 10.1016/j.critrevonc.2014.06.003. [Epub ahead of print] Review. PubMed PMID: 25028151.

3: Khan G, Moss RA, Braiteh F, Saltzman M. Proactive strategies for regorafenib in metastatic colorectal cancer: implications for optimal patient management. Cancer Manag Res. 2014 Mar 4;6:93-103. doi: 10.2147/CMAR.S52217. eCollection 2014. Review. PubMed PMID: 24623990; PubMed Central PMCID: PMC3949557.

4: De Wit M, Boers-Doets CB, Saettini A, Vermeersch K, de Juan CR, Ouwerkerk J, Raynard SS, Bazin A, Cremolini C. Prevention and management of adverse events related to regorafenib. Support Care Cancer. 2014 Mar;22(3):837-46. doi: 10.1007/s00520-013-2085-z. Epub 2013 Dec 14. Review. PubMed PMID: 24337717; PubMed Central PMCID: PMC3913844.

5: Lyseng-Williamson KA. Regorafenib: a guide to its use in advanced gastrointestinal stromal tumor (GIST) after failure of imatinib and sunitinib. BioDrugs. 2013 Oct;27(5):525-31. doi: 10.1007/s40259-013-0061-2. Review. PubMed PMID: 23975637.

6: Regorafenib (Stivarga) for metastatic colorectal cancer and GIST. Med Lett Drugs Ther. 2013 Apr 29;55(1415):e36. Review. PubMed PMID: 23836345.

7: Sirohi B, Philip DS, Shrikhande SV. Regorafenib: carving a niche in the crowded therapeutic landscape. Expert Rev Anticancer Ther. 2013 Apr;13(4):385-93. doi: 10.1586/era.13.12. Review. PubMed PMID: 23560833.

8: Davis SL, Eckhardt SG, Messersmith WA, Jimeno A. The development of regorafenib and its current and potential future role in cancer therapy. Drugs Today (Barc). 2013 Feb;49(2):105-15. doi: 10.1358/dot.2013.49.2.1930525. Review. PubMed PMID: 23462625.

9: Roman D, Whiteside R. Regorafenib: Adding to the Armamentarium for Refractory Colorectal Cancer and GIST. J Adv Pract Oncol. 2013 Mar;4(2):118-22. Review. PubMed PMID: 25031991; PubMed Central PMCID: PMC4093419.

10: Aprile G, Macerelli M, Giuliani F. Regorafenib for gastrointestinal malignancies : from preclinical data to clinical results of a novel multi-target inhibitor. BioDrugs. 2013 Jun;27(3):213-24. doi: 10.1007/s40259-013-0014-9. Review. PubMed PMID: 23435872.

11: Strumberg D, Schultheis B. Regorafenib for cancer. Expert Opin Investig Drugs. 2012 Jun;21(6):879-89. doi: 10.1517/13543784.2012.684752. Review. PubMed PMID: 22577890.



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