Cabozantinib
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Identification
- Summary
Cabozantinib is a tyrosine kinase inhibitor used to treat advanced renal cell carcinoma, hepatocellular carcinoma, and medullary thyroid cancer.
- Brand Names
- Cabometyx, Cometriq
- Generic Name
- Cabozantinib
- DrugBank Accession Number
- DB08875
- Background
Cabozantinib was first approved in 2012 and is a non-specific tyrosine kinase inhibitor. It was initially approved in the US under the brand name Cometriq, which is indicated for the treatment of metastatic medullary thyroid cancer.6 In 2016, a capsule formulation (Cabometyx) was approved for the treatment of advanced renal cell carcinoma, and this same formulation gained additional approval in both the US and Canada in 2019 for the treatment of hepatocellular carcinoma in previously treated patients.7,8
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
- Weight
- Average: 501.514
Monoisotopic: 501.169999048 - Chemical Formula
- C28H24FN3O5
- Synonyms
- Cabozantinib
- External IDs
- BMS 907351
- BMS907351
- XL 184
- XL-184
- XL184
Pharmacology
- Indication
Cabozantinib is indicated for the treatment of progressive, metastatic medullary thyroid cancer.6 It is also indicated for the treatment of advanced renal cell carcinoma and for hepatocellular carcinoma in patients previously treated with sorafenib.7,8
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used in combination to treat Advanced renal cell carcinoma Regimen in combination with: Nivolumab (DB09035) •••••••••••• •••••••• •••••• Treatment of Advanced renal cell carcinoma •••••••••••• •••••• Treatment of Advanced renal cell carcinoma •••••••••••• ••••• •••• •• •••••••••••• ••••• ••••••••• ••••• •••••• Treatment of Advanced renal cell carcinoma •••••••••••• •••••••••• ••••••• •••• ••••••••• •••••• Treatment of Hepatocellular carcinoma •••••••••••• •••••••••• ••••••• •••• ••••••••• •••••• - Contraindications & Blackbox Warnings
- Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API
- Pharmacodynamics
Cabozantinib suppresses metastasis, angiogenesis, and oncognesis by inhibiting receptor tyrosine kinases.
- Mechanism of action
Cabozantinib inhibits specific receptor tyrosine kinases such as VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL, RET, MET, and TIE-2.
Target Actions Organism AHepatocyte growth factor receptor antagonistHumans AVascular endothelial growth factor receptor 2 antagonistHumans AProto-oncogene tyrosine-protein kinase receptor Ret antagonistHumans - Absorption
After oral administration, peak plasma concentration was achieved in 2-5 hours.
- Volume of distribution
The volume of distribution is 349L.
- Protein binding
Cabozantinib 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 elimination
Cabozantinib is eliminated mostly by the feces (54%) and also by the urine (27%).
- Half-life
Cabozantinib has a long half-life of 55 hours.
- Clearance
At steady state, the clearance is 4.4 L/hr.
- Adverse Effects
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.
- Toxicity
Cabozantinib carries a warning of serious gastrointestinal fistulas and perforations, and potentially fatal hemoptysis and gastrointestinal hemorrhage.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Cabozantinib can be increased when it is combined with Abametapir. Abatacept The metabolism of Cabozantinib can be increased when combined with Abatacept. Abrocitinib The metabolism of Abrocitinib can be decreased when combined with Cabozantinib. Acenocoumarol The metabolism of Cabozantinib can be decreased when combined with Acenocoumarol. Acetaminophen The serum concentration of Acetaminophen can be increased when it is combined with Cabozantinib. - Food Interactions
- Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase levels of cabozantinib.
- Avoid St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce serum levels of cabozantinib.
- Take on an empty stomach. Separate the administration of cabozantinib from food by at least 1 hour before or 2 hours after eating.
- Take with a full glass of water.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Product Ingredients
Ingredient UNII CAS InChI Key Cabozantinib malate DR7ST46X58 1140909-48-3 HFCFMRYTXDINDK-WNQIDUERSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Cabometyx Tablet 40 mg Oral Ipsen Biopharmaceuticals, Inc. 2018-10-10 Not applicable Canada Cabometyx Tablet, film coated 20 mg Oral Ipsen Pharma 2020-12-16 Not applicable EU Cabometyx Tablet 40 mg/1 Oral Exelixis, Inc. 2016-04-25 Not applicable US Cabometyx Tablet 20 mg Oral Ipsen Biopharmaceuticals, Inc. 2018-10-10 Not applicable Canada Cabometyx Tablet, film coated 60 mg Oral Ipsen Pharma 2020-12-16 Not applicable EU - Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Cometriq Cabozantinib malate (80 mg/1) + Cabozantinib malate (20 mg/1) Capsule; Kit Oral Exelixis, Inc. 2012-11-29 Not applicable US COMETRIQ Cabozantinib malate (20 MG) + Cabozantinib malate (80 MG) Capsule Oral Ipsen Pharma 2016-05-06 Not applicable Italy COMETRIQ Cabozantinib malate (20 MG) + Cabozantinib malate (80 MG) Capsule Oral Ipsen Pharma 2014-10-06 Not applicable Italy Cometriq Cabozantinib malate (80 mg/1) + Cabozantinib malate (20 mg/1) Capsule; Kit Oral Exelixis, Inc. 2012-11-29 Not applicable US Cometriq Cabozantinib malate (20 mg/1) + Cabozantinib malate (80 mg/1) Kit Oral Catalent Pharma Solutions, Llc 2012-11-29 2018-01-19 US
Categories
- ATC Codes
- L01EX07 — Cabozantinib
- Drug Categories
- Amides
- Amines
- Aniline Compounds
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- Cytochrome P-450 CYP2C8 Inhibitors
- Cytochrome P-450 CYP2C8 Inhibitors (weak)
- Cytochrome P-450 CYP2C9 Substrates
- Cytochrome P-450 CYP2C9 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Kinase Inhibitor
- Narrow Therapeutic Index Drugs
- Protein Kinase Inhibitors
- Receptor Protein-Tyrosine Kinases, antagonists & inhibitors
- Tyrosine Kinase Inhibitors
- Chemical TaxonomyProvided by Classyfire
- Description
- This 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.
- Kingdom
- Organic compounds
- Super Class
- Organic oxygen compounds
- Class
- Organooxygen compounds
- Sub Class
- Ethers
- Direct Parent
- Diarylethers
- Alternative Parents
- Quinolines and derivatives / Anilides / Phenoxy compounds / Anisoles / N-arylamides / Alkyl aryl ethers / Fluorobenzenes / Pyridines and derivatives / Aryl fluorides / Cyclopropanecarboxylic acids and derivatives show 8 more
- Substituents
- Alkyl aryl ether / Anilide / Anisole / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Azacycle / Benzenoid / Carbonyl group / Carboxamide group show 21 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- organofluorine compound, dicarboxylic acid diamide, aromatic ether, quinolines (CHEBI:72317)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 1C39JW444G
- CAS number
- 849217-68-1
- InChI Key
- ONIQOQHATWINJY-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
- N'1-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
- 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
References
- General References
- 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. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- Escudier B, Lougheed JC, Albiges L: Cabozantinib for the treatment of renal cell carcinoma. Expert Opin Pharmacother. 2016 Dec;17(18):2499-2504. doi: 10.1080/14656566.2016.1258059. Epub 2016 Nov 22. [Article]
- FDA Approved Drug Products: Cometriq (cabozantinib) oral capsules [Link]
- FDA Approved Drug Products: Cabometyx (cabozantinib) oral tablets [Link]
- Health Canada Product Monograph: Cabometyx (cabozantinib) oral tablets [Link]
- External Links
- KEGG Drug
- D10062
- PubChem Compound
- 25102847
- PubChem Substance
- 347827806
- ChemSpider
- 25948202
- BindingDB
- 50021574
- 1363268
- ChEBI
- 72317
- ChEMBL
- CHEMBL2105717
- ZINC
- ZINC000070466416
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Cabozantinib
- FDA label
- Download (194 KB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Active Not Recruiting Not Available Liver Cancer 1 somestatus stop reason just information to hide Not Available Active Not Recruiting Not Available Renal Cell Carcinoma (RCC) 1 somestatus stop reason just information to hide Not Available Approved for Marketing Not Available Thyroid Gland Medullary Carcinoma 1 somestatus stop reason just information to hide Not Available Completed Not Available Locally Advanced or Metastatic Renal Cell Carcinoma 1 somestatus stop reason just information to hide Not Available Completed Not Available Renal Cell Carcinoma (RCC) 3 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral 25.340 mg Tablet Oral 20 mg Tablet Oral 20 mg/1 Tablet Oral 40 mg/1 Tablet Oral 40 mg Tablet Oral 60 mg Tablet Oral 60 mg/1 Tablet, film coated Oral 20 mg Tablet, film coated Oral 40 mg Tablet, film coated Oral 60 mg Capsule Oral Capsule Oral 20 mg/1 Capsule Oral 20 MG Capsule; kit Oral Kit Oral - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8877776 No 2014-11-04 2030-10-08 US US7579473 No 2009-08-25 2024-09-24 US US8497284 No 2013-07-30 2024-09-24 US US9724342 No 2017-08-08 2033-07-09 US US9717720 No 2017-08-01 2032-02-10 US US10039757 No 2018-08-07 2031-07-18 US US10034873 No 2018-07-31 2031-07-18 US US11098015 No 2021-08-24 2030-01-15 US US11091439 No 2021-08-17 2030-01-15 US US11091440 No 2021-08-17 2030-01-15 US US11141413 No 2021-10-12 2037-04-17 US US11298349 No 2012-02-10 2032-02-10 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility COMETRIQ is practically insoluble in water. From FDA label. - Predicted Properties
Property Value Source Water Solubility 0.00199 mg/mL ALOGPS logP 4.01 ALOGPS logP 4.66 Chemaxon logS -5.4 ALOGPS pKa (Strongest Acidic) 13.46 Chemaxon pKa (Strongest Basic) 5.9 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 98.78 Å2 Chemaxon Rotatable Bond Count 8 Chemaxon Refractivity 136.12 m3·mol-1 Chemaxon Polarizability 51.49 Å3 Chemaxon Number of Rings 5 Chemaxon Bioavailability 1 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 208.07274 predictedDeepCCS 1.0 (2019) [M+H]+ 210.4683 predictedDeepCCS 1.0 (2019) [M+Na]+ 216.38084 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General 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 signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1, SRC, GRB2, STAT3 or the adapter GAB1. Recruitment of these downstream effectors by MET leads to the activation of several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. The RAS-ERK activation is associated with the morphogenetic effects while PI3K/AKT coordinates prosurvival effects. During embryonic development, MET signaling plays a role in gastrulation, development and migration of neuronal precursors, angiogenesis and kidney formation. During skeletal muscle development, it is crucial for the migration of muscle progenitor cells and for the proliferation of secondary myoblasts (By similarity). In adults, participates in wound healing as well as organ regeneration and tissue remodeling. Promotes also differentiation and proliferation of hematopoietic cells. May regulate cortical bone osteogenesis (By similarity)
- Specific Function
- ATP binding
- Gene Name
- MET
- Uniprot ID
- P08581
- Uniprot Name
- Hepatocyte growth factor receptor
- Molecular Weight
- 155540.035 Da
References
- 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. [Article]
- 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. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General 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 domain, such as isoform 2 and isoform 3, may function as decoy receptors for VEGFA, VEGFC and/or VEGFD. Isoform 2 plays an important role as negative regulator of VEGFA- and VEGFC-mediated lymphangiogenesis by limiting the amount of free VEGFA and/or VEGFC and preventing their binding to FLT4. Modulates FLT1 and FLT4 signaling by forming heterodimers. Binding of vascular growth factors to isoform 1 leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, reorganization of the actin cytoskeleton and activation of PTK2/FAK1. Required for VEGFA-mediated induction of NOS2 and NOS3, leading to the production of the signaling molecule nitric oxide (NO) by endothelial cells. Phosphorylates PLCG1. Promotes phosphorylation of FYN, NCK1, NOS3, PIK3R1, PTK2/FAK1 and SRC
- Specific Function
- ATP binding
- Gene Name
- KDR
- Uniprot ID
- P35968
- Uniprot Name
- Vascular endothelial growth factor receptor 2
- Molecular Weight
- 151525.555 Da
References
- 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. [Article]
- 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. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation in response to glia cell line-derived growth family factors (GDNF, NRTN, ARTN, PSPN and GDF15) (PubMed:20064382, PubMed:20616503, PubMed:20702524, PubMed:21357690, PubMed:21454698, PubMed:24560924, PubMed:28846097, PubMed:28846099, PubMed:28953886, PubMed:31118272). In contrast to most receptor tyrosine kinases, RET requires not only its cognate ligands but also coreceptors, for activation (PubMed:21994944, PubMed:23333276, PubMed:28846097, PubMed:28846099, PubMed:28953886). GDNF ligands (GDNF, NRTN, ARTN, PSPN and GDF15) first bind their corresponding GDNFR coreceptors (GFRA1, GFRA2, GFRA3, GFRA4 and GFRAL, respectively), triggering RET autophosphorylation and activation, leading to activation of downstream signaling pathways, including the MAPK- and AKT-signaling pathways (PubMed:21994944, PubMed:23333276, PubMed:24560924, PubMed:25242331, PubMed:28846097, PubMed:28846099, PubMed:28953886). Acts as a dependence receptor via the GDNF-GFRA1 signaling: in the presence of the ligand GDNF in somatotrophs within pituitary, promotes survival and down regulates growth hormone (GH) production, but triggers apoptosis in absence of GDNF (PubMed:20616503, PubMed:21994944). Required for the molecular mechanisms orchestration during intestine organogenesis via the ARTN-GFRA3 signaling: involved in the development of enteric nervous system and renal organogenesis during embryonic life, and promotes the formation of Peyer's patch-like structures, a major component of the gut-associated lymphoid tissue (By similarity). Mediates, through interaction with GDF15-receptor GFRAL, GDF15-induced cell-signaling in the brainstem which triggers an aversive response, characterized by nausea, vomiting, and/or loss of appetite in response to various stresses (PubMed:28846097, PubMed:28846099, PubMed:28953886). Modulates cell adhesion via its cleavage by caspase in sympathetic neurons and mediates cell migration in an integrin (e.g. ITGB1 and ITGB3)-dependent manner (PubMed:20702524, PubMed:21357690). Also active in the absence of ligand, triggering apoptosis through a mechanism that requires receptor intracellular caspase cleavage (PubMed:21357690). Triggers the differentiation of rapidly adapting (RA) mechanoreceptors (PubMed:20064382). Involved in the development of the neural crest (By similarity). Regulates nociceptor survival and size (By similarity). Phosphorylates PTK2/FAK1 (PubMed:21454698)
- Specific Function
- ATP binding
- Gene Name
- RET
- Uniprot ID
- P07949
- Uniprot Name
- Proto-oncogene tyrosine-protein kinase receptor Ret
- Molecular Weight
- 124317.465 Da
References
- 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. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
- Specific Function
- 1,8-cineole 2-exo-monooxygenase activity
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Nguyen L, Holland J, Miles D, Engel C, Benrimoh N, O'Reilly T, Lacy S: Pharmacokinetic (PK) drug interaction studies of cabozantinib: Effect of CYP3A inducer rifampin and inhibitor ketoconazole on cabozantinib plasma PK and effect of cabozantinib on CYP2C8 probe substrate rosiglitazone plasma PK. J Clin Pharmacol. 2015 Sep;55(9):1012-23. doi: 10.1002/jcph.510. Epub 2015 Jun 2. [Article]
- Gerendash BS, Creel PA: Practical management of adverse events associated with cabozantinib treatment in patients with renal-cell carcinoma. Onco Targets Ther. 2017 Oct 19;10:5053-5064. doi: 10.2147/OTT.S145295. eCollection 2017. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and steroids (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:15766564, PubMed:19965576, PubMed:7574697, PubMed:9866708). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Exhibits low catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes bisallylic hydroxylation and hydroxylation with double-bond migration of polyunsaturated fatty acids (PUFA) (PubMed:9435160, PubMed:9866708). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan (PubMed:25994031)
- Specific Function
- (R)-limonene 6-monooxygenase activity
- Gene Name
- CYP2C9
- Uniprot ID
- P11712
- Uniprot Name
- Cytochrome P450 2C9
- Molecular Weight
- 55627.365 Da
References
- Cabozantinib FDA Label [File]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:15766564, PubMed:19965576, PubMed:7574697). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772). Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847). Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316)
- Specific Function
- arachidonic acid epoxygenase activity
- Gene Name
- CYP2C8
- Uniprot ID
- P10632
- Uniprot Name
- Cytochrome P450 2C8
- Molecular Weight
- 55824.275 Da
References
- Escudier B, Lougheed JC, Albiges L: Cabozantinib for the treatment of renal cell carcinoma. Expert Opin Pharmacother. 2016 Dec;17(18):2499-2504. doi: 10.1080/14656566.2016.1258059. Epub 2016 Nov 22. [Article]
Drug created at May 13, 2013 00:12 / Updated at November 01, 2023 04:04