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Identification
NameCabozantinib
Accession NumberDB08875
TypeSmall Molecule
GroupsApproved
Description

Cabozantinib was approved in 2012 and is a non-specific tyrosine kinase inhibitor. It is marketed as Cometriq, which is indicated for the treatment of metastatic medullary thyroid cancer. It’s label includes a black box warning of gastrointestinal perforations, fistulas, and hemorrhage. The FDA approved cabozantinib as Cabometyx for patients with advanced renal cell carcinoma in April 2016.

Structure
Thumb
SynonymsNot Available
External Identifiers
  • BMS 907351
  • BMS907351
  • XL 184
  • XL-184
  • XL184
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
CometriqkitExelixis, Inc.2012-11-292016-04-05Us
Cometriqcapsule20 mg/1oralExelixis, Inc.2012-11-292016-04-05Us
Cometriqcapsule20 mg/1oralExelixis, Inc.2012-11-292016-04-05Us
CometriqkitExelixis, Inc.2012-11-292016-04-05Us
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International BrandsNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Cabozantinib malate
1140909-48-3
Thumb
  • InChI Key: HFCFMRYTXDINDK-WNQIDUERSA-N
  • Monoisotopic Mass: 635.191522341
  • Average Mass: 635.601
DBSALT001762
Categories
UNII1C39JW444G
CAS number849217-68-1
WeightAverage: 501.514
Monoisotopic: 501.169999048
Chemical FormulaC28H24FN3O5
InChI KeyONIQOQHATWINJY-UHFFFAOYSA-N
InChI
InChI=1S/C28H24FN3O5/c1-35-24-15-21-22(16-25(24)36-2)30-14-11-23(21)37-20-9-7-19(8-10-20)32-27(34)28(12-13-28)26(33)31-18-5-3-17(29)4-6-18/h3-11,14-16H,12-13H2,1-2H3,(H,31,33)(H,32,34)
IUPAC Name
SMILES
COC1=CC2=C(C=C1OC)C(OC1=CC=C(NC(=O)C3(CC3)C(=O)NC3=CC=C(F)C=C3)C=C1)=CC=N2
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as diarylethers. These are organic compounds containing the dialkyl ether functional group, with the formula ROR', where R and R' are aryl groups.
KingdomOrganic compounds
Super ClassOrganic oxygen compounds
ClassOrganooxygen compounds
Sub ClassEthers
Direct ParentDiarylethers
Alternative Parents
Substituents
  • Diaryl ether
  • Quinoline
  • Anilide
  • Phenoxy compound
  • Anisole
  • Phenol ether
  • N-arylamide
  • Alkyl aryl ether
  • Fluorobenzene
  • Halobenzene
  • Aryl fluoride
  • Aryl halide
  • Cyclopropanecarboxylic acid or derivatives
  • Benzenoid
  • Pyridine
  • Monocyclic benzene moiety
  • Heteroaromatic compound
  • Carboxamide group
  • Secondary carboxylic acid amide
  • Azacycle
  • Organoheterocyclic compound
  • Carboxylic acid derivative
  • Organonitrogen compound
  • Carbonyl group
  • Organic oxide
  • Organic nitrogen compound
  • Hydrocarbon derivative
  • Organofluoride
  • Organohalogen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationFor the treatment of metastatic medullary thyroid cancer and for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.
PharmacodynamicsCabozantinib suppresses metastasis, angiogenesis, and oncognesis by inhibiting receptor tyrosine kinases.
Mechanism of actionCabozantinib inhibits specific receptor tyrosine kinases such as VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL, RET, MET, and TIE-2.
Related Articles
AbsorptionAfter oral administration, peak plasma concentration was achieved in 2-5 hours.
Volume of distribution

The volume of distribution is 349L.

Protein bindingCabozantinib has extensive plasma protein binding (≥ 99.7%).
Metabolism

Cabozantinib is metabolized mostly by CYP3A4 and, to a minor extent, by CYP2C9. Both enzyme produce an N-oxide metabolite.

Route of eliminationCabozantinib is eliminated mostly by the feces (54%) and also by the urine (27%).
Half lifeCabozantinib has a long half-life of 55 hours.
Clearance

At steady state, the clearance is 4.4 L/hr.

ToxicityCabozantinib has a black box warning of serious gastrointestinal fistulas and perforations, and potentially fatal hemoptysis and gastrointestinal hemorrhage.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal AbsorptionNot AvailableNot Available
Blood Brain BarrierNot AvailableNot Available
Caco-2 permeableNot AvailableNot Available
P-glycoprotein substrateNot AvailableNot Available
P-glycoprotein inhibitor INot AvailableNot Available
P-glycoprotein inhibitor IINot AvailableNot Available
Renal organic cation transporterNot AvailableNot Available
CYP450 2C9 substrateNot AvailableNot Available
CYP450 2D6 substrateNot AvailableNot Available
CYP450 3A4 substrateNot AvailableNot Available
CYP450 1A2 substrateNot AvailableNot Available
CYP450 2C9 inhibitorNot AvailableNot Available
CYP450 2D6 inhibitorNot AvailableNot Available
CYP450 2C19 inhibitorNot AvailableNot Available
CYP450 3A4 inhibitorNot AvailableNot Available
CYP450 inhibitory promiscuityNot AvailableNot Available
Ames testNot AvailableNot Available
CarcinogenicityNot AvailableNot Available
BiodegradationNot AvailableNot Available
Rat acute toxicityNot AvailableNot applicable
hERG inhibition (predictor I)Not AvailableNot Available
hERG inhibition (predictor II)Not AvailableNot Available
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Capsuleoral20 mg/1
Kit
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7579473 No2004-09-242024-09-24Us
US8877776 No2010-10-082030-10-08Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
water solubilityCOMETRIQ is practically insoluble in water.From FDA label.
Predicted Properties
PropertyValueSource
Water Solubility0.00199 mg/mLALOGPS
logP4.01ALOGPS
logS-5.4ALOGPS
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General References
  1. Durante C, Russo D, Verrienti A, Filetti S: XL184 (cabozantinib) for medullary thyroid carcinoma. Expert Opin Investig Drugs. 2011 Mar;20(3):407-413. doi: 10.1517/13543784.2011.559163. [PubMed:21314233 ]
  2. Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, Hammers H, Hutson TE, Lee JL, Peltola K, Roth BJ, Bjarnason GA, Geczi L, Keam B, Maroto P, Heng DY, Schmidinger M, Kantoff PW, Borgman-Hagey A, Hessel C, Scheffold C, Schwab GM, Tannir NM, Motzer RJ: Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015 Nov 5;373(19):1814-23. doi: 10.1056/NEJMoa1510016. Epub 2015 Sep 25. [PubMed:26406150 ]
  3. Krajewska J, Olczyk T, Jarzab B: Cabozantinib for the treatment of progressive metastatic medullary thyroid cancer. Expert Rev Clin Pharmacol. 2016;9(1):69-79. doi: 10.1586/17512433.2016.1102052. Epub 2015 Nov 4. [PubMed:26536165 ]
  4. Grullich C: Cabozantinib: a MET, RET, and VEGFR2 tyrosine kinase inhibitor. Recent Results Cancer Res. 2014;201:207-14. doi: 10.1007/978-3-642-54490-3_12. [PubMed:24756794 ]
External Links
ATC CodesL01XE26
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (194 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AprepitantThe serum concentration of Cabozantinib can be increased when it is combined with Aprepitant.
AtazanavirThe serum concentration of Cabozantinib can be increased when it is combined with Atazanavir.
BexaroteneThe serum concentration of Cabozantinib can be decreased when it is combined with Bexarotene.
BoceprevirThe serum concentration of Cabozantinib can be increased when it is combined with Boceprevir.
BosentanThe serum concentration of Cabozantinib can be decreased when it is combined with Bosentan.
CarbamazepineThe serum concentration of Cabozantinib can be decreased when it is combined with Carbamazepine.
CeritinibThe serum concentration of Cabozantinib can be increased when it is combined with Ceritinib.
ClarithromycinThe serum concentration of Cabozantinib can be increased when it is combined with Clarithromycin.
CobicistatThe serum concentration of Cabozantinib can be increased when it is combined with Cobicistat.
ConivaptanThe serum concentration of Cabozantinib can be increased when it is combined with Conivaptan.
DabrafenibThe serum concentration of Cabozantinib can be decreased when it is combined with Dabrafenib.
DarunavirThe serum concentration of Cabozantinib can be increased when it is combined with Darunavir.
DasatinibThe serum concentration of Cabozantinib can be increased when it is combined with Dasatinib.
DeferasiroxThe serum concentration of Cabozantinib can be decreased when it is combined with Deferasirox.
DexamethasoneThe serum concentration of Cabozantinib can be decreased when it is combined with Dexamethasone.
EnzalutamideThe serum concentration of Cabozantinib can be decreased when it is combined with Enzalutamide.
FluconazoleThe metabolism of Cabozantinib can be decreased when combined with Fluconazole.
FosaprepitantThe serum concentration of Cabozantinib can be increased when it is combined with Fosaprepitant.
FosphenytoinThe serum concentration of Cabozantinib can be decreased when it is combined with Fosphenytoin.
Fusidic AcidThe serum concentration of Cabozantinib can be increased when it is combined with Fusidic Acid.
IdelalisibThe serum concentration of Cabozantinib can be increased when it is combined with Idelalisib.
IndinavirThe serum concentration of Cabozantinib can be increased when it is combined with Indinavir.
ItraconazoleThe serum concentration of Cabozantinib can be increased when it is combined with Itraconazole.
IvacaftorThe serum concentration of Cabozantinib can be increased when it is combined with Ivacaftor.
KetoconazoleThe serum concentration of Cabozantinib can be increased when it is combined with Ketoconazole.
LuliconazoleThe serum concentration of Cabozantinib can be increased when it is combined with Luliconazole.
MifepristoneThe serum concentration of Cabozantinib can be increased when it is combined with Mifepristone.
MitotaneThe serum concentration of Cabozantinib can be decreased when it is combined with Mitotane.
NefazodoneThe serum concentration of Cabozantinib can be increased when it is combined with Nefazodone.
NelfinavirThe serum concentration of Cabozantinib can be increased when it is combined with Nelfinavir.
NetupitantThe serum concentration of Cabozantinib can be increased when it is combined with Netupitant.
PalbociclibThe serum concentration of Cabozantinib can be increased when it is combined with Palbociclib.
PamidronateThe risk or severity of adverse effects can be increased when Cabozantinib is combined with Pamidronate.
PhenobarbitalThe serum concentration of Cabozantinib can be decreased when it is combined with Phenobarbital.
PhenytoinThe serum concentration of Cabozantinib can be decreased when it is combined with Phenytoin.
PosaconazoleThe serum concentration of Cabozantinib can be increased when it is combined with Posaconazole.
PrimidoneThe serum concentration of Cabozantinib can be decreased when it is combined with Primidone.
RifabutinThe serum concentration of Cabozantinib can be decreased when it is combined with Rifabutin.
RifampicinThe serum concentration of Cabozantinib can be decreased when it is combined with Rifampicin.
RifapentineThe serum concentration of Cabozantinib can be decreased when it is combined with Rifapentine.
RitonavirThe serum concentration of Cabozantinib can be increased when it is combined with Ritonavir.
SaquinavirThe serum concentration of Cabozantinib can be increased when it is combined with Saquinavir.
SiltuximabThe serum concentration of Cabozantinib can be decreased when it is combined with Siltuximab.
SimeprevirThe serum concentration of Cabozantinib can be increased when it is combined with Simeprevir.
St. John's WortThe serum concentration of Cabozantinib can be decreased when it is combined with St. John's Wort.
StiripentolThe serum concentration of Cabozantinib can be increased when it is combined with Stiripentol.
TelaprevirThe serum concentration of Cabozantinib can be increased when it is combined with Telaprevir.
TelithromycinThe serum concentration of Cabozantinib can be increased when it is combined with Telithromycin.
TocilizumabThe serum concentration of Cabozantinib can be decreased when it is combined with Tocilizumab.
VoriconazoleThe serum concentration of Cabozantinib can be increased when it is combined with Voriconazole.
Food Interactions
  • Avoid grapefruit juice. Combination may increase levels of cabozantinib. Also avoid all other strong CYP3A4 inhibitors.

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
General Function:
Protein tyrosine kinase activity
Specific Function:
Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand. Regulates many physiological processes including proliferation, scattering, morphogenesis and survival. Ligand binding at the cell surface induces autophosphorylation of MET on its intracellular domain that provides docking sites for downstream sig...
Gene Name:
MET
Uniprot ID:
P08581
Molecular Weight:
155540.035 Da
References
  1. Kurzrock R, Sherman SI, Ball DW, Forastiere AA, Cohen RB, Mehra R, Pfister DG, Cohen EE, Janisch L, Nauling F, Hong DS, Ng CS, Ye L, Gagel RF, Frye J, Muller T, Ratain MJ, Salgia R: Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol. 2011 Jul 1;29(19):2660-6. doi: 10.1200/JCO.2010.32.4145. Epub 2011 May 23. [PubMed:21606412 ]
  2. Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, Qian F, Chu F, Bentzien F, Cancilla B, Orf J, You A, Laird AD, Engst S, Lee L, Lesch J, Chou YC, Joly AH: Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011 Dec;10(12):2298-308. doi: 10.1158/1535-7163.MCT-11-0264. Epub 2011 Sep 16. [PubMed:21926191 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
General Function:
Vascular endothelial growth factor-activated receptor activity
Specific Function:
Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and embryonic hematopoiesis. Promotes proliferation, survival, migration and differentiation of endothelial cells. Promotes reorganization of the actin cytoskeleton. Isoforms lacking a transmembrane domai...
Gene Name:
KDR
Uniprot ID:
P35968
Molecular Weight:
151525.555 Da
References
  1. Kurzrock R, Sherman SI, Ball DW, Forastiere AA, Cohen RB, Mehra R, Pfister DG, Cohen EE, Janisch L, Nauling F, Hong DS, Ng CS, Ye L, Gagel RF, Frye J, Muller T, Ratain MJ, Salgia R: Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol. 2011 Jul 1;29(19):2660-6. doi: 10.1200/JCO.2010.32.4145. Epub 2011 May 23. [PubMed:21606412 ]
  2. Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, Qian F, Chu F, Bentzien F, Cancilla B, Orf J, You A, Laird AD, Engst S, Lee L, Lesch J, Chou YC, Joly AH: Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011 Dec;10(12):2298-308. doi: 10.1158/1535-7163.MCT-11-0264. Epub 2011 Sep 16. [PubMed:21926191 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
General Function:
Transmembrane receptor protein tyrosine kinase activity
Specific Function:
Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation upon binding with glial cell derived neurotrophic factor family ligands. Phosphorylates PTK2/FAK1. Regulates both cell death/survival balance and positional information. Required for the molecular mechanisms orchestration during in...
Gene Name:
RET
Uniprot ID:
P07949
Molecular Weight:
124317.465 Da
References
  1. Kurzrock R, Sherman SI, Ball DW, Forastiere AA, Cohen RB, Mehra R, Pfister DG, Cohen EE, Janisch L, Nauling F, Hong DS, Ng CS, Ye L, Gagel RF, Frye J, Muller T, Ratain MJ, Salgia R: Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol. 2011 Jul 1;29(19):2660-6. doi: 10.1200/JCO.2010.32.4145. Epub 2011 May 23. [PubMed:21606412 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
no
Actions
substrate
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References

From FDA label.

Kind
Protein
Organism
Human
Pharmacological action
no
Actions
substrate
General Function:
Steroid hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenyto...
Gene Name:
CYP2C9
Uniprot ID:
P11712
Molecular Weight:
55627.365 Da
References

From FDA label.

Comments
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Drug created on May 12, 2013 18:12 / Updated on May 01, 2016 02:29