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Identification
NameRegorafenib
Accession NumberDB08896
Typesmall molecule
Groupsapproved
Description

Regorafenib is an orally-administered inhibitor of multiple kinases. It is used for the treatment of metastatic colorectal cancer and advanced gastrointestinal stromal tumours. FDA approved on September 27, 2012.

Structure
Thumb
SynonymsNot Available
SaltsNot Available
Brand names
NameCompany
Stivarga Bayer HealthCare Pharmaceuticals
Brand mixturesNot Available
Categories
CAS number755037-03-7
WeightAverage: 482.815
Monoisotopic: 482.076880893
Chemical FormulaC21H15ClF4N4O3
InChI KeyFNHKPVJBJVTLMP-UHFFFAOYSA-N
InChI
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)
IUPAC Name
4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide
SMILES
CNC(=O)C1=CC(OC2=CC(F)=C(NC(=O)NC3=CC=C(Cl)C(=C3)C(F)(F)F)C=C2)=CC=N1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganooxygen Compounds
ClassEthers
SubclassDiarylethers
Direct parentDiarylethers
Alternative parentsPyridinecarboxamides; Phenol Ethers; Fluorobenzenes; Chlorobenzenes; Aryl Fluorides; Aryl Chlorides; Secondary Carboxylic Acid Amides; Enolates; Polyamines; Carboxylic Acids; Organofluorides; Organochlorides; Alkyl Fluorides
Substituentspyridinecarboxamide; pyridine carboxylic acid or derivative; phenol ether; fluorobenzene; chlorobenzene; pyridine; aryl chloride; aryl halide; benzene; aryl fluoride; secondary carboxylic acid amide; carboxamide group; carboxylic acid; carboxylic acid derivative; enolate; polyamine; organofluoride; organochloride; organohalogen; amine; organonitrogen compound; alkyl halide; alkyl fluoride
Classification descriptionThis compound belongs to the diarylethers. These are organic compounds containing the dialkyl ether functional group, with the formula ROR', where R and R' are aryl groups.
Pharmacology
IndicationRegorafenib is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy. Regorafenib is also indicated for the treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate.
PharmacodynamicsNot Available
Mechanism of actionRegorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment. In in vitro biochemical or cellular assays, regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E , SAPK2, PTK5, and Abl at concentrations of regorafenib that have been achieved clinically. In in vivo models, regorafenib demonstrated anti-angiogenic activity in a rat tumor model, and inhibition of tumor growth as well as anti-metastatic activity in several mouse xenograft models including some for human colorectal carcinoma.
AbsorptionCmax = 2.5 μg/mL; Tmax = 4 hours; AUC = 70.4 μg*h/mL; Cmax, steady-state = 3.9 μg/mL; AUC, steady-state = 58.3 μg*h/mL; The mean relative bioavailability of tablets compared to an oral solution is 69% to 83%.
Volume of distribution

Regorafenib undergoes enterohepatic circulation with multiple plasma concentration peaks observed across the 24-hour dosing interval.

Protein bindingRegorafenib is highly bound (99.5%) to human plasma proteins.
Metabolism

Regorafenib is metabolized by CYP3A4 and UGT1A9. The main circulating metabolites of regorafenib measured at steady-state in human plasma are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), both of them having similar in vitro pharmacological activity and steady-state concentrations as regorafenib. M-2 and M-5 are highly protein bound (99.8% and 99.95%, respectively).

Route of eliminationApproximately 71% of a radiolabeled dose was excreted in feces (47% as parent compound, 24% as metabolites) and 19% of the dose was excreted in urine (17% as glucuronides) within 12 days after administration of a radiolabeled oral solution at a dose of 120 mg.
Half lifeRegorafenib, 160 mg oral dose = 28 hours (14 - 58 hours); M2 metabolite, 160 mg oral dose = 25 hours (14-32 hours); M5 metabolite, 160 mg oral dose = 51 hours (32-72 hours);
ClearanceNot Available
ToxicityThe most common adverse reactions (≥20%) are asthenia/fatigue, HFSR, diarrhea, decreased appetite/food intake, hypertension, mucositis, dysphonia, and infection, pain (not otherwise specified), decreased weight, gastrointestinal and abdominal pain, rash, fever, and nausea
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9649
Blood Brain Barrier + 0.851
Caco-2 permeable - 0.5138
P-glycoprotein substrate Non-substrate 0.5086
P-glycoprotein inhibitor I Non-inhibitor 0.7141
P-glycoprotein inhibitor II Non-inhibitor 0.9359
Renal organic cation transporter Non-inhibitor 0.8938
CYP450 2C9 substrate Non-substrate 0.6569
CYP450 2D6 substrate Non-substrate 0.8212
CYP450 3A4 substrate Non-substrate 0.5341
CYP450 1A2 substrate Inhibitor 0.6168
CYP450 2C9 substrate Non-inhibitor 0.6171
CYP450 2D6 substrate Non-inhibitor 0.9145
CYP450 2C19 substrate Inhibitor 0.637
CYP450 3A4 substrate Non-inhibitor 0.7339
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.6629
Ames test Non AMES toxic 0.8143
Carcinogenicity Non-carcinogens 0.8684
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 2.7885 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9488
hERG inhibition (predictor II) Non-inhibitor 0.6415
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
TabletOral40 mg
PricesNot Available
Patents
CountryPatent NumberApprovedExpires (estimated)
Canada23157152010-06-222018-12-22
Canada25266362012-10-022024-05-19
Canada25495582010-08-312020-01-12
Properties
Statesolid
Experimental Properties
PropertyValueSource
water solubilityInsoluble FDA label
Predicted Properties
PropertyValueSource
water solubility1.02e-03 g/lALOGPS
logP4.53ALOGPS
logP4.49ChemAxon
logS-5.7ALOGPS
pKa (strongest acidic)10.52ChemAxon
pKa (strongest basic)2.02ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count3ChemAxon
hydrogen donor count3ChemAxon
polar surface area92.35ChemAxon
rotatable bond count6ChemAxon
refractivity114.73ChemAxon
polarizability41.23ChemAxon
number of rings3ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD10138
ChEBI68647
ChEMBLCHEMBL1946170
RxListhttp://www.rxlist.com/stivarga-drug.htm
Drugs.comhttp://www.drugs.com/cdi/regorafenib.html
WikipediaRegorafenib
ATC CodesL01XE21
AHFS Codes
  • 10:00
PDB EntriesNot Available
FDA labelshow(457 KB)
MSDSshow(479 KB)
Interactions
Drug Interactions
Drug
CarbamazepineStrong CYP3A4 inducers may decrease levels of regorafenib.
ClarithromycinStrong CYP3A4 inhibitors may increase levels of regorafenib.
IrinotecanRegorafenib may increase levels of irinotecan, a UGT1A1 substrate.
ItraconazoleStrong CYP3A4 inhibitors may increase levels of regorafenib.
KetoconazoleStrong CYP3A4 inhibitors may increase levels of regorafenib.
PhenobarbitalStrong CYP3A4 inducers may decrease levels of regorafenib.
PhenytoinStrong CYP3A4 inducers may decrease levels of regorafenib.
PosaconazoleStrong CYP3A4 inhibitors may increase levels of regorafenib.
RifampicinStrong CYP3A4 inducers may decrease levels of regorafenib.
St. John's WortStrong CYP3A4 inducers may decrease levels of regorafenib.
TelithromycinStrong CYP3A4 inhibitors may increase levels of regorafenib.
VoriconazoleStrong CYP3A4 inhibitors may increase levels of regorafenib.
Food Interactions
  • When taken with a high-fat meal, AUC increased by 48% and decreased mean AUC of M2 and M5 metabolites by 20% and 51% respectively.

Targets

1. Proto-oncogene tyrosine-protein kinase receptor Ret

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Proto-oncogene tyrosine-protein kinase receptor Ret P07949 Details

References:

  1. FDA label

2. Vascular endothelial growth factor receptor 1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Vascular endothelial growth factor receptor 1 P17948 Details

References:

  1. FDA label

3. Vascular endothelial growth factor receptor 2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Vascular endothelial growth factor receptor 2 P35968 Details

References:

  1. FDA label

4. Vascular endothelial growth factor receptor 3

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Vascular endothelial growth factor receptor 3 P35916 Details

References:

  1. FDA label

5. Mast/stem cell growth factor receptor Kit

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Mast/stem cell growth factor receptor Kit P10721 Details

References:

  1. FDA label

6. Platelet-derived growth factor receptor alpha

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Platelet-derived growth factor receptor alpha P16234 Details

References:

  1. FDA label

7. Platelet-derived growth factor receptor beta

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Platelet-derived growth factor receptor beta P09619 Details

References:

  1. FDA label

8. Fibroblast growth factor receptor 1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Fibroblast growth factor receptor 1 P11362 Details

References:

  1. FDA label

9. Fibroblast growth factor receptor 2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Fibroblast growth factor receptor 2 P21802 Details

References:

  1. FDA label

10. Angiopoietin-1 receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Angiopoietin-1 receptor Q02763 Details

References:

  1. FDA label

11. Discoidin domain-containing receptor 2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Discoidin domain-containing receptor 2 Q16832 Details

References:

  1. FDA label

12. High affinity nerve growth factor receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
High affinity nerve growth factor receptor P04629 Details

References:

  1. FDA label

13. Ephrin type-A receptor 2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Ephrin type-A receptor 2 P29317 Details

References:

  1. FDA label

14. RAF proto-oncogene serine/threonine-protein kinase

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
RAF proto-oncogene serine/threonine-protein kinase P04049 Details

References:

  1. FDA label

15. Serine/threonine-protein kinase B-raf

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Serine/threonine-protein kinase B-raf P15056 Details

References:

  1. FDA label

16. Mitogen-activated protein kinase 11

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Mitogen-activated protein kinase 11 Q15759 Details

References:

  1. FDA label

17. Tyrosine-protein kinase FRK

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Tyrosine-protein kinase FRK P42685 Details

References:

  1. FDA label

18. Tyrosine-protein kinase ABL1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Tyrosine-protein kinase ABL1 P00519 Details

References:

  1. FDA label

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. FDA label

2. UDP-glucuronosyltransferase 1-9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 1-9 O60656 Details

References:

  1. FDA label

3. Cytochrome P450 2C8

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C8 P10632 Details

References:

  1. FDA label

4. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

References:

  1. FDA label

5. Cytochrome P450 2B6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2B6 P20813 Details

References:

  1. FDA label

6. Cytochrome P450 2C19

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C19 P33261 Details

References:

  1. FDA label

7. UDP-glucuronosyltransferase 1-1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 1-1 P22309 Details

References:

  1. FDA label

Transporters

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. FDA label

2. ATP-binding cassette sub-family G member 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
ATP-binding cassette sub-family G member 2 Q9UNQ0 Details

References:

  1. FDA label

Comments
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Drug created on June 03, 2013 16:30 / Updated on September 16, 2013 18:11