Drug Details

General Information of the Drug (ID: DR6166)
Name
Regorafenib
Synonyms
BAY 73-4506; Regorafenibum; Stivarga; 4-(4-(3-(4-Chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-N-methylpicolinamide; BAY73-4506; Regorafenib (BAY 73-4506); UNII-24T2A1DOYB; 4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide; BAY-73-4506; 24T2A1DOYB; CHEMBL1946170; CHEBI:68647; Stivarga (TN); BAY73-4506 hydrochloride; Regorafenib [USAN:INN]; 755037-03-7
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Molecular Type
Small molecule
Disease Colorectal cancer [ICD-11: 2B91] Approved [1]
Structure
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2D MOL

3D MOL

ADMET Property
Absorption AUC
The area under the plot of plasma concentration (AUC) of drug is 70.4 mgh/L
Absorption Cmax
The maximum plasma concentration (Cmax) of drug is 2.5 mg/L
Absorption Tmax
The time to maximum plasma concentration (Tmax) is 4 h
Half-life
The concentration or amount of drug in body reduced by one-half in 28 hours
Metabolism
The drug is metabolized via the CYP3A4 and UGT1A9
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Formula
C21H15ClF4N4O3
PubChem CID
11167602
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
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)
InChIKey
FNHKPVJBJVTLMP-UHFFFAOYSA-N
CAS Number
CAS 755037-03-7
ChEBI ID
CHEBI:68647
TTD Drug ID
D09GDD
DrugBank ID
DB08896
Combinatorial Therapeutic Effect(s) Validated Clinically or Experimentally
    α. A List of Natural Product(s) Able to Enhance the Efficacy of This Drug
          Chlorogenic acid      Imperata cylindrica     Click to Show/Hide the Molecular Data of This NP
                 Augmenting Drug Sensitivity     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [2]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Up-regulation Expression BAX  Molecule Info 
Pathway MAP
Down-regulation Expression BCL-2  Molecule Info 
Pathway MAP
Down-regulation Expression BCL-xL  Molecule Info 
Pathway MAP
Up-regulation Expression CASP7  Molecule Info 
Pathway MAP
                    In-vitro Model PLC/PRF/5 CVCL_0485 Adult hepatocellular carcinoma Homo sapiens
Hep-G2 CVCL_0027 Hepatocellular carcinoma Homo sapiens
                    Experimental
                    Result(s)		 Co-treatment with Regorafenib and CGA enhanced Regorafenib action, reducing its cytotoxicity in HCC cells.
          Silibinin      Carduus marianus     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [3]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Phosphorylation AKT1  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation EIF4EBP1  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation S6K1  Molecule Info 
Pathway MAP
                    In-vitro Model SW48 CVCL_1724 Colon adenocarcinoma Homo sapiens
GEO CVCL_0271 Colon carcinoma Homo sapiens
LIM1215 CVCL_2574 Colon adenocarcinoma Homo sapiens
HCT 15 CVCL_0292 Colon adenocarcinoma Homo sapiens
HCT 116 CVCL_0291 Colon carcinoma Homo sapiens
SW480 CVCL_0546 Colon adenocarcinoma Homo sapiens
LoVo CVCL_0399 Colon adenocarcinoma Homo sapiens
SW620 CVCL_0547 Colon adenocarcinoma Homo sapiens
                    Experimental
                    Result(s)		 The combined treatment with regorafenib and silybin induced synergistic anti-proliferative and apoptotic effects by blocking PI3K/AKT/mTOR intracellular pathway.
          Toosendanin      Melia azedarach     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [4]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression DVL2  Molecule Info 
Pathway MAP
Up-regulation Phosphorylation GSK-3B  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation STAT3  Molecule Info 
Pathway MAP
Up-regulation Expression WWOX  Molecule Info 
Pathway MAP
                    In-vitro Model MHCC97-L CVCL_4973 Adult hepatocellular carcinoma Homo sapiens
                    Experimental
                    Result(s)		 TSN and RGF combination (TRC) synergistically inhibited the proliferation and migration of MHCC-97L cells. The upregulation of WWOX (WW-domain containing oxidoreductase) played a vital role in the HCC cell growth treated with TRC.
Target and Pathway
Target(s) Proto-oncogene c-Ret (RET)  Molecule Info  [5]
Tyrosine-protein kinase Kit (KIT)  Molecule Info  [5]
Vascular endothelial growth factor receptor 2 (KDR)  Molecule Info  [5]
KEGG Pathway Ras signaling pathway Click to Show/Hide
2 Rap1 signaling pathway
3 Cytokine-cytokine receptor interaction
4 Endocytosis
5 PI3K-Akt signaling pathway
6 Hematopoietic cell lineage
7 Melanogenesis
8 Pathways in cancer
9 Acute myeloid leukemia
10 Central carbon metabolism in cancer
11 Thyroid cancer
12 VEGF signaling pathway
13 Focal adhesion
14 Proteoglycans in cancer
NetPath Pathway IL3 Signaling Pathway Click to Show/Hide
2 IL4 Signaling Pathway
3 KitReceptor Signaling Pathway
4 IL2 Signaling Pathway
Panther Pathway Angiogenesis Click to Show/Hide
2 VEGF signaling pathway
Pathway Interaction Database C-MYB transcription factor network Click to Show/Hide
2 Signaling events mediated by Stem cell factor receptor (c-Kit)
3 Signaling events regulated by Ret tyrosine kinase
4 Posttranslational regulation of adherens junction stability and dissassembly
5 HIF-2-alpha transcription factor network
6 Beta3 integrin cell surface interactions
7 Signaling events mediated by TCPTP
8 SHP2 signaling
9 S1P1 pathway
10 VEGF and VEGFR signaling network
11 Integrins in angiogenesis
12 Signaling events mediated by VEGFR1 and VEGFR2
13 Notch-mediated HES/HEY network
Reactome PIP3 activates AKT signaling Click to Show/Hide
2 Regulation of KIT signaling
3 Constitutive Signaling by Aberrant PI3K in Cancer
4 RAF/MAP kinase cascade
5 Neurophilin interactions with VEGF and VEGFR
6 VEGF binds to VEGFR leading to receptor dimerization
7 Integrin cell surface interactions
8 EPHA-mediated growth cone collapse
9 VEGFA-VEGFR2 Pathway
10 VEGFR2 mediated cell proliferation
WikiPathways Kit receptor signaling pathway Click to Show/Hide
2 Differentiation Pathway
3 Signaling by SCF-KIT
4 PIP3 activates AKT signaling
5 Cardiac Progenitor Differentiation
6 miR-targeted genes in muscle cell - TarBase
7 miR-targeted genes in lymphocytes - TarBase
8 miR-targeted genes in epithelium - TarBase
9 SIDS Susceptibility Pathways
10 Dopaminergic Neurogenesis
11 Focal Adhesion
12 Nifedipine Activity
13 Signaling by VEGF
14 Angiogenesis
References
Reference 1 URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5891).
Reference 2 Chlorogenic Acid Improves the Regorafenib Effects in Human Hepatocellular Carcinoma Cells. Int J Mol Sci. 2018 May 19;19(5):1518.
Reference 3 Regorafenib in combination with silybin as a novel potential strategy for the treatment of metastatic colorectal cancer. Oncotarget. 2017 Aug 7;8(40):68305-68316.
Reference 4 Synergistic effect of toosendanin and regorafenib against cell proliferation and migration by regulating WWOX signaling pathway in hepatocellular carcinoma. Phytother Res. 2021 May 31.
Reference 5 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
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