Explore a selection of our essential drug information below, or:
Identification
- Summary
Tivozanib is a kinase inhibitor to treat adult patients with renal cell carcinoma (RCC) who have failed prior systemic therapies or experienced relapsed disease.
- Brand Names
- Fotivda
- Generic Name
- Tivozanib
- DrugBank Accession Number
- DB11800
- Background
Renal cell carcinoma (RCC) is responsible for 3% of cancer cases2 and is one of the 10 most common cancers in adults. The average age of diagnosis is between age 65 to 74.10 Tivozanib, also known as FOTIVDA, is a kinase inhibitor developed to treat adult patients with relapsed or refractory advanced renal cell carcinoma (RCC) after prior failed systemic therapies. It was approved on March 10, 2021 by the FDA. Marketed by Aveo Oncology, tivozanib is a promising therapy for individuals with RCC who have not been treated successfully with other therapies.9
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Tivozanib (DB11800)
- Weight
- Average: 454.863
Monoisotopic: 454.104397445 - Chemical Formula
- C22H19ClN4O5
- Synonyms
- Tivozanib
- External IDs
- AV 951
- AV-951
- AV951
- KIL-8951
- KRN 951
- KRN-951
Pharmacology
- Indication
Tivozanib is approved in the USA for the treatment of relapsed or refractory renal cell carcinoma in adult patients who have undergone two or more systemic therapies.9 In the UK and other countries, it is indicated as first-line therapy of adults with advanced renal cell carcinoma (RCC) and VEGFR and mTOR pathway inhibitor-naïve patients after disease progression following one previous treatment with cytokine therapy for advanced disease.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 Treatment of Advanced renal cell carcinoma •••••••••••• ••••• ••••• •••••••••••••••• ••••••• ••••••••••• ••••• ••••• •••••••• •••••••• •••• ••••••••••••••• Treatment of Advanced renal cell carcinoma •••••••••••• ••••• Treatment of Renal cell adenocarcinoma •••••••••••• ••••• ••••••• Treatment of Renal cell adenocarcinoma •••••••••••• ••••• ••••••• - 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
Tivozanib inhibits growth factor receptors, treating renal cell carcinoma. In mice and rats, tivozanib inhibits tumour angiogenesis, tumour growth, and vascular permeability.9 Tivozanib was shown to frequently cause hypertension in clinical trials; hypertension must be managed before initiating therapy. Cardiac QT segment prolongation was reported in a tivozanib cardiac safety study, however the reactions were not considered clinically serious.8 In clinical studies, levels of serum soluble VEGFR2 (sVEGFR2) decreased with time and this effect increased with tivozanib exposure, and sVEGFR2 may serve as a pharmacodynamic marker of VEGFR inhibition.13
- Mechanism of action
The VHL mutation-HIF upregulation-VEGF transcription is the main pathway implicated in the growth of renal cell carcinoma. Vascular endothelial growth factor receptors (VEGFR receptors) are important targets for tyrosine kinase inhibitors, which halt the growth of tumours.7 Tivozanib is a tyrosine kinase inhibitor that exerts its actions by inhibiting the phosphorylation of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2 and VEGFR-3 and inhibits other kinases such as c-kit and platelet derived growth factor beta (PDGFR β). The above actions inhibit tumour growth and progression, treating renal cell carcinoma.7,9
Target Actions Organism AVascular endothelial growth factor receptor 1 inhibitorHumans AVascular endothelial growth factor receptor 2 inhibitorHumans AVascular endothelial growth factor receptor 3 inhibitorHumans AMast/stem cell growth factor receptor Kit inhibitorHumans APlatelet-derived growth factor receptor beta inhibitorHumans UReceptor-type tyrosine-protein kinase FLT3 inhibitorHumans UPlatelet-derived growth factor receptor alpha inhibitorHumans UProtein-tyrosine kinase 6 Not Available Humans UAngiopoietin-1 receptor Not Available Humans UFibroblast growth factor receptor 1 inhibitorHumans UHepatocyte growth factor receptor inhibitorHumans - Absorption
The median Tmax of tivozanib is 10 hours, however, can range from 3 to 24 hours.9 A pharmacokinetic study in 8 healthy subjects revealed a Cmax and AUC for radiolabeled tivozanib of 12.1 ± 5.67 ng/mL and 1084 ± 417.0 ng·h/mL, respectively.3 Steady-state tivozanib concentrations are achieved at concentrations 6-7 times higher the normal dose.13
- Volume of distribution
Tivozanib has an apparent volume of distribution (V/F) of 123 L.9
- Protein binding
In vitro, the protein binding of tivozanib is mainly bound to albumin at a rate of ≥ 99%.9
- Metabolism
Tivozanib is primarily metabolized by CYP3A4.4,8 After oral ingestion of a radiolabeled 1.34 mg dose of tivozanib in healthy volunteers, unchanged tivozanib accounted for 90% of the radioactive drug detected in serum.9
- Route of elimination
Tivozanib is primarily excreted in the feces. After oral ingestion of a radiolabeled 1.34 mg dose of tivozanib in healthy volunteers, 79% of the administered dose was found in the feces (with 26% unchanged) and 12% was found in the urine solely as metabolites.3,9
- Half-life
The half-life of tivozanib is about 111 hours according to prescribing information.9 Information from clinical studies reveals a half-life of 4-5 days.3,13
- Clearance
The apparent clearance (CL/F) of tivozanib is approximately 0.75 L/h.9
- 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
LD50 information for tivozanib is not readily available in the literature, however the European Medicines Agency (EMA) assessment report indicates the oral maximum tolerated dose (MTD) in mice was 524 mg/kg; doses ≥ 750 mg/kg led to severe and lethal effects. In rats, the oral MTD was to 276 mg/kg; at doses ≥ 369 mg/kg, severe effects and death occurred.12
In tivozanib monotherapy studies, two patients received overdoses of tivozanib. One volunteer with a prior history of hypertension experienced aggravated uncontrolled hypertension that resulted in death after taking 3 doses of 1340 microgram tivozanib in one day (total of 4020 micrograms). A second patient patient ingested two doses of 1340 microgram tivozanib in one day (total of 2680 micrograms), and experienced no adverse effects. Carefully control blood pressure before starting tivozanib; regularly monitor blood pressure during treatment. In the case of a confirmed or suspected overdose, discontinue tivozanib, monitor the patient closely, and provide supportive treatment as necessary. No antidote exists for an overdose with tivozanib.8
- 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 softwareAbemaciclib Tivozanib may decrease the excretion rate of Abemaciclib which could result in a higher serum level. Abrocitinib The serum concentration of Tivozanib can be increased when it is combined with Abrocitinib. Acetaminophen The metabolism of Tivozanib can be increased when combined with Acetaminophen. Adagrasib The serum concentration of Tivozanib can be increased when it is combined with Adagrasib. Afatinib Tivozanib may decrease the excretion rate of Afatinib which could result in a higher serum level. - Food Interactions
- Take with or without food.
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 Tivozanib hydrochloride 8A9H4VK35Z 682745-41-1 RQXMKRRBJITKRN-UHFFFAOYSA-N - International/Other Brands
- Fotivda (AVEO Oncology)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Fotivda Capsule 890 ?g Oral Recordati Netherlands B.V. 2020-12-16 Not applicable EU 
Fotivda Capsule 1.34 mg/1 Oral Aveo Pharmaceuticals, Inc. 2021-03-10 Not applicable US 
Fotivda Capsule 1340 ?g Oral Recordati Netherlands B.V. 2020-12-16 Not applicable EU Fotivda Capsule 0.89 mg/1 Oral Aveo Pharmaceuticals, Inc. 2021-03-10 Not applicable US
Categories
- ATC Codes
- L01EK03 — Tivozanib
- Drug Categories
- Amides
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- BCRP/ABCG2 Inhibitors
- Benzene Derivatives
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Substrates
- Enzyme Inhibitors
- Heterocyclic Compounds, Fused-Ring
- Kinase Inhibitor
- P-glycoprotein substrates
- Protein Kinase Inhibitors
- Receptors, Vascular Endothelial Growth Factor, antagonists & inhibitors
- Tyrosine Kinase Inhibitors
- Vascular endothelial growth factor receptor (VEGFR) 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 / N-phenylureas / Anisoles / Phenoxy compounds / Alkyl aryl ethers / Chlorobenzenes / Pyridines and derivatives / Imidolactams / Aryl chlorides / Isoxazoles show 10 more
- Substituents
- Alkyl aryl ether / Anisole / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Azole / Benzenoid / Carbonic acid derivative / Carbonyl group show 22 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- 172030934T
- CAS number
- 475108-18-0
- InChI Key
- SPMVMDHWKHCIDT-UHFFFAOYSA-N
- InChI
- InChI=1S/C22H19ClN4O5/c1-12-8-21(27-32-12)26-22(28)25-16-5-4-13(9-15(16)23)31-18-6-7-24-17-11-20(30-3)19(29-2)10-14(17)18/h4-11H,1-3H3,(H2,25,26,27,28)
- IUPAC Name
- 1-{2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-3-(5-methyl-1,2-oxazol-3-yl)urea
- SMILES
- COC1=C(OC)C=C2C(OC3=CC(Cl)=C(NC(=O)NC4=NOC(C)=C4)C=C3)=CC=NC2=C1
References
- Synthesis Reference
Liu, M. X., Hu, L. X., Wang, X. W., & Zhu, H. D. (2011). Synthesis of Anti-Cancer Targeted Therapies Drug Tivozanib. Advanced Materials Research, 396–398, 1490–1492. https://doi.org/10.4028/www.scientific.net/amr.396-398.1490
- General References
- Cairns P: Renal cell carcinoma. Cancer Biomark. 2010;9(1-6):461-73. doi: 10.3233/CBM-2011-0176. [Article]
- Pallagani L, Choudhary GR, Himanshu P, Madduri VKS, Singh M, Gupta P, Shrivastava N, Baid G, Meenakshi R, Aasma N, Pareek P, Sanjeev M: Epidemiology and Clinicopathological Profile of Renal Cell Carcinoma: A Review from Tertiary Care Referral Centre. J Kidney Cancer VHL. 2021 Jan 20;8(1):1-6. doi: 10.15586/jkcvhl.2021.154. eCollection 2021. [Article]
- Cotreau MM, Hale CL, Jacobson L, Oelke CS, Strahs AL, Kochan RG, Sanga M, Slichenmyer W, Vargo DL: Absorption, Metabolism, and Excretion of [(14) C]-Tivozanib, a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Healthy Male Participants: A Phase I, Open-Label, Mass-Balance Study. Clin Pharmacol Drug Dev. 2012 Jul;1(3):102-9. doi: 10.1177/2160763X12447303. [Article]
- Wang J, Bruin MAC, Gan C, Lebre MC, Rosing H, Beijnen JH, Schinkel AH: Brain accumulation of tivozanib is restricted by ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein) in mice. Int J Pharm. 2020 May 15;581:119277. doi: 10.1016/j.ijpharm.2020.119277. Epub 2020 Mar 28. [Article]
- Cotreau MM, Massmanian L, Strahs AL, Slichenmyer W, Vargo DL: The effect of food on the pharmacokinetics of tivozanib hydrochloride. Clin Pharmacol Drug Dev. 2014 Mar;3(2):158-62. doi: 10.1002/cpdd.76. Epub 2013 Oct 30. [Article]
- Kim ES: Tivozanib: First Global Approval. Drugs. 2017 Nov;77(17):1917-1923. doi: 10.1007/s40265-017-0825-y. [Article]
- Jacob A, Shook J, Hutson TE: Tivozanib, a highly potent and selective inhibitor of VEGF receptor tyrosine kinases, for the treatment of metastatic renal cell carcinoma. Future Oncol. 2020 Oct;16(28):2147-2164. doi: 10.2217/fon-2020-0443. Epub 2020 Jul 21. [Article]
- EMC Summary of Product Characteristics: Fotivda (tivozanib hydrochloride monohydrate) oral capsules [Link]
- FDA Approved Drug Products: FOTIVDA (tivozanib) capsules, for oral use [Link]
- Cancer.org: Key Statistics About Kidney Cancer [Link]
- Cayman Chem safety data sheet: Tivozanib hydrate [Link]
- EMA Assessment Report: Fotivda (tivozanib) oral capsules [Link]
- AVEO Oncology: Tivozanib hydrochloride pharmacokinetic/pharmacodynamic analysis of blood pressure and soluble vascular endothelial growth factor receptor 2 (sVEGFR2) in patients with advanced renal cell carcinoma [Link]
- External Links
- Human Metabolome Database
- HMDB0304847
- PubChem Compound
- 9911830
- PubChem Substance
- 347828149
- ChemSpider
- 8087481
- BindingDB
- 50331095
- 2534233
- ChEBI
- 91327
- ChEMBL
- CHEMBL1289494
- ZINC
- ZINC000001489430
- PDBe Ligand
- AV9
- Wikipedia
- Tivozanib
- PDB Entries
- 4ase / 8bem
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 Terminated Treatment Solid Tumors 1 somestatus stop reason just information to hide Not Available Withdrawn Treatment Stage II Renal Cell Carcinoma / Stage III Renal Cell Carcinoma 1 somestatus stop reason just information to hide 3 Active Not Recruiting Treatment Renal Cell Carcinoma (RCC) 1 somestatus stop reason just information to hide 3 Completed Treatment Advanced Renal Cell Carcinoma 2 somestatus stop reason just information to hide 3 Completed Treatment Renal Cell Carcinoma (RCC) 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 0.89 mg/1 Capsule Oral 1.34 mg/1 Capsule Oral 1340 MCG Capsule Oral 1340 ?g Capsule Oral 890 MCG Capsule Oral 890 ?g - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US6821987 No 2004-11-23 2022-04-26 US US7166722 No 2007-01-23 2023-11-16 US US11504365 No 2019-11-05 2039-11-05 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 220-233 https://store.apolloscientific.co.uk/product/tivozanib boiling point (°C) 550.4 ± 50.0 https://www.chemsrc.com/en/cas/475108-18-0_754439.html water solubility <1g/mL https://www.mybiosource.com/inhibitor/tivozanib-av-951/384260 logP 4.31 https://www.chemsrc.com/en/cas/475108-18-0_754439.html Caco2 permeability 0.5 https://www.ema.europa.eu/en/documents/assessment-report/fotivda-epar-public-assessment-report_en.pdf pKa 11.74±0.70 https://www.chemicalbook.com/ChemicalProductProperty_EN_CB82484655.htm - Predicted Properties
Property Value Source Water Solubility 0.0521 mg/mL ALOGPS logP 4.25 ALOGPS logP 4.22 Chemaxon logS -3.9 ALOGPS pKa (Strongest Acidic) 8.27 Chemaxon pKa (Strongest Basic) 5.89 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 107.74 Å2 Chemaxon Rotatable Bond Count 6 Chemaxon Refractivity 120.85 m3·mol-1 Chemaxon Polarizability 44.26 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-0a4i-1000900000-1dfa1d11166c36a4a943 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0532-9002000000-d0a41edc82be03b3c000 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-0002-9001400000-a52f0b88d31018c21c60 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0100-9035400000-5a7bdf826f62e405189f Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-00c0-9207600000-fa74583c3bf9d795493d Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-00lr-9300000000-7c8d7c35cf34cfc85bd5 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 205.81651 predictedDeepCCS 1.0 (2019) [M+H]+ 208.17451 predictedDeepCCS 1.0 (2019) [M+Na]+ 214.26767 predictedDeepCCS 1.0 (2019)
Targets
Build, predict & validate machine-learning models
Use our structured and evidence-based datasets to unlock newinsights and accelerate drug research.
Use our structured and evidence-based datasets to unlock new insights and accelerate drug research.
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFB and PGF, and plays an essential role in the development of embryonic vasculature, the regulation of angiogenesis, cell survival, cell migration, macrophage function, chemotaxis, and cancer cell invasion. Acts as a positive regulator of postnatal retinal hyaloid vessel regression (By similarity). May play an essential role as a negative regulator of embryonic angiogenesis by inhibiting excessive proliferation of endothelial cells. Can promote endothelial cell proliferation, survival and angiogenesis in adulthood. Its function in promoting cell proliferation seems to be cell-type specific. Promotes PGF-mediated proliferation of endothelial cells, proliferation of some types of cancer cells, but does not promote proliferation of normal fibroblasts (in vitro). Has very high affinity for VEGFA and relatively low protein kinase activity; may function as a negative regulator of VEGFA signaling by limiting the amount of free VEGFA and preventing its binding to KDR. Modulates KDR signaling by forming heterodimers with KDR. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leading to activation of phosphatidylinositol kinase and the downstream signaling pathway. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Phosphorylates SRC and YES1, and may also phosphorylate CBL. Promotes phosphorylation of AKT1 at 'Ser-473'. Promotes phosphorylation of PTK2/FAK1 (PubMed:16685275)
- Specific Function
- Atp binding
- Gene Name
- FLT1
- Uniprot ID
- P17948
- Uniprot Name
- Vascular endothelial growth factor receptor 1
- Molecular Weight
- 150767.185 Da
References
- Wang J, Bruin MAC, Gan C, Lebre MC, Rosing H, Beijnen JH, Schinkel AH: Brain accumulation of tivozanib is restricted by ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein) in mice. Int J Pharm. 2020 May 15;581:119277. doi: 10.1016/j.ijpharm.2020.119277. Epub 2020 Mar 28. [Article]
- Salgia NJ, Zengin ZB, Pal SK: Tivozanib in renal cell carcinoma: a new approach to previously treated disease. Ther Adv Med Oncol. 2020 May 22;12:1758835920923818. doi: 10.1177/1758835920923818. eCollection 2020. [Article]
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- FDA Approved Drug Products: FOTIVDA (tivozanib) capsules, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- 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
- Wang J, Bruin MAC, Gan C, Lebre MC, Rosing H, Beijnen JH, Schinkel AH: Brain accumulation of tivozanib is restricted by ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein) in mice. Int J Pharm. 2020 May 15;581:119277. doi: 10.1016/j.ijpharm.2020.119277. Epub 2020 Mar 28. [Article]
- Salgia NJ, Zengin ZB, Pal SK: Tivozanib in renal cell carcinoma: a new approach to previously treated disease. Ther Adv Med Oncol. 2020 May 22;12:1758835920923818. doi: 10.1177/1758835920923818. eCollection 2020. [Article]
- FDA Approved Drug Products: FOTIVDA (tivozanib) capsules, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardiovascular system during embryonic development. Promotes proliferation, survival and migration of endothelial cells, and regulates angiogenic sprouting. Signaling by activated FLT4 leads to enhanced production of VEGFC, and to a lesser degree VEGFA, thereby creating a positive feedback loop that enhances FLT4 signaling. Modulates KDR signaling by forming heterodimers. The secreted isoform 3 may function as a decoy receptor for VEGFC and/or VEGFD and play an important role as a negative regulator of VEGFC-mediated lymphangiogenesis and angiogenesis. Binding of vascular growth factors to isoform 1 or isoform 2 leads to the activation of several signaling cascades; isoform 2 seems to be less efficient in signal transduction, because it has a truncated C-terminus and therefore lacks several phosphorylation sites. Mediates activation of the MAPK1/ERK2, MAPK3/ERK1 signaling pathway, of MAPK8 and the JUN signaling pathway, and of the AKT1 signaling pathway. Phosphorylates SHC1. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Promotes phosphorylation of MAPK8 at 'Thr-183' and 'Tyr-185', and of AKT1 at 'Ser-473'
- Specific Function
- Atp binding
- Gene Name
- FLT4
- Uniprot ID
- P35916
- Uniprot Name
- Vascular endothelial growth factor receptor 3
- Molecular Weight
- 152755.94 Da
References
- Wang J, Bruin MAC, Gan C, Lebre MC, Rosing H, Beijnen JH, Schinkel AH: Brain accumulation of tivozanib is restricted by ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein) in mice. Int J Pharm. 2020 May 15;581:119277. doi: 10.1016/j.ijpharm.2020.119277. Epub 2020 Mar 28. [Article]
- Salgia NJ, Zengin ZB, Pal SK: Tivozanib in renal cell carcinoma: a new approach to previously treated disease. Ther Adv Med Oncol. 2020 May 22;12:1758835920923818. doi: 10.1177/1758835920923818. eCollection 2020. [Article]
- FDA Approved Drug Products: FOTIVDA (tivozanib) capsules, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Tyrosine-protein kinase that acts as a cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. In response to KITLG/SCF binding, KIT can activate several signaling pathways. Phosphorylates PIK3R1, PLCG1, SH2B2/APS and CBL. Activates the AKT1 signaling pathway by phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Activated KIT also transmits signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3, STAT5A and STAT5B. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KIT signaling is modulated by protein phosphatases, and by rapid internalization and degradation of the receptor. Activated KIT promotes phosphorylation of the protein phosphatases PTPN6/SHP-1 and PTPRU, and of the transcription factors STAT1, STAT3, STAT5A and STAT5B. Promotes phosphorylation of PIK3R1, CBL, CRK (isoform Crk-II), LYN, MAPK1/ERK2 and/or MAPK3/ERK1, PLCG1, SRC and SHC1
- Specific Function
- Atp binding
- Gene Name
- KIT
- Uniprot ID
- P10721
- Uniprot Name
- Mast/stem cell growth factor receptor Kit
- Molecular Weight
- 109863.655 Da
References
- Kalathil SG, Wang K, Hutson A, Iyer R, Thanavala Y: Tivozanib mediated inhibition of c-Kit/SCF signaling on Tregs and MDSCs and reversal of tumor induced immune suppression correlates with survival of HCC patients. Oncoimmunology. 2020 Sep 30;9(1):1824863. doi: 10.1080/2162402X.2020.1824863. [Article]
- Yalcin S, Lacin S: Impact of tivozanib on patient outcomes in treatment of advanced renal cell carcinoma. Cancer Manag Res. 2019 Aug 16;11:7779-7785. doi: 10.2147/CMAR.S206105. eCollection 2019. [Article]
- FDA Approved Drug Products: FOTIVDA (tivozanib) capsules, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Tyrosine-protein kinase that acts as a cell-surface receptor for homodimeric PDGFB and PDGFD and for heterodimers formed by PDGFA and PDGFB, and plays an essential role in the regulation of embryonic development, cell proliferation, survival, differentiation, chemotaxis and migration. Plays an essential role in blood vessel development by promoting proliferation, migration and recruitment of pericytes and smooth muscle cells to endothelial cells. Plays a role in the migration of vascular smooth muscle cells and the formation of neointima at vascular injury sites. Required for normal development of the cardiovascular system. Required for normal recruitment of pericytes (mesangial cells) in the kidney glomerulus, and for normal formation of a branched network of capillaries in kidney glomeruli. Promotes rearrangement of the actin cytoskeleton and the formation of membrane ruffles. Binding of its cognate ligands - homodimeric PDGFB, heterodimers formed by PDGFA and PDGFB or homodimeric PDGFD -leads to the activation of several signaling cascades; the response depends on the nature of the bound ligand and is modulated by the formation of heterodimers between PDGFRA and PDGFRB. Phosphorylates PLCG1, PIK3R1, PTPN11, RASA1/GAP, CBL, SHC1 and NCK1. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, mobilization of cytosolic Ca(2+) and the activation of protein kinase C. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to the activation of the AKT1 signaling pathway. Phosphorylation of SHC1, or of the C-terminus of PTPN11, creates a binding site for GRB2, resulting in the activation of HRAS, RAF1 and down-stream MAP kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation and activation of SRC family kinases. Promotes phosphorylation of PDCD6IP/ALIX and STAM. Receptor signaling is down-regulated by protein phosphatases that dephosphorylate the receptor and its down-stream effectors, and by rapid internalization of the activated receptor
- Specific Function
- Atp binding
- Gene Name
- PDGFRB
- Uniprot ID
- P09619
- Uniprot Name
- Platelet-derived growth factor receptor beta
- Molecular Weight
- 123966.895 Da
References
- Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, Tomczak P, Lyulko O, Alyasova A, Harza M, Kogan M, Alekseev BY, Sternberg CN, Szczylik C, Cella D, Ivanescu C, Krivoshik A, Strahs A, Esteves B, Berkenblit A, Hutson TE: Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol. 2013 Oct 20;31(30):3791-9. doi: 10.1200/JCO.2012.47.4940. Epub 2013 Sep 9. [Article]
- Lierman E, Lahortiga I, Van Miegroet H, Mentens N, Marynen P, Cools J: The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. Haematologica. 2007 Jan;92(1):27-34. [Article]
- FDA Approved Drug Products: CUBICIN (daptomycin) injection [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Tyrosine-protein kinase that acts as a cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells. Promotes phosphorylation of SHC1 and AKT1, and activation of the downstream effector MTOR. Promotes activation of RAS signaling and phosphorylation of downstream kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation of FES, FER, PTPN6/SHP, PTPN11/SHP-2, PLCG1, and STAT5A and/or STAT5B. Activation of wild-type FLT3 causes only marginal activation of STAT5A or STAT5B. Mutations that cause constitutive kinase activity promote cell proliferation and resistance to apoptosis via the activation of multiple signaling pathways
- Specific Function
- Atp binding
- Gene Name
- FLT3
- Uniprot ID
- P36888
- Uniprot Name
- Receptor-type tyrosine-protein kinase FLT3
- Molecular Weight
- 112902.51 Da
References
- Yalcin S, Lacin S: Impact of tivozanib on patient outcomes in treatment of advanced renal cell carcinoma. Cancer Manag Res. 2019 Aug 16;11:7779-7785. doi: 10.2147/CMAR.S206105. eCollection 2019. [Article]
- Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, Tomczak P, Lyulko O, Alyasova A, Harza M, Kogan M, Alekseev BY, Sternberg CN, Szczylik C, Cella D, Ivanescu C, Krivoshik A, Strahs A, Esteves B, Berkenblit A, Hutson TE: Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol. 2013 Oct 20;31(30):3791-9. doi: 10.1200/JCO.2012.47.4940. Epub 2013 Sep 9. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Tyrosine-protein kinase that acts as a cell-surface receptor for PDGFA, PDGFB and PDGFC and plays an essential role in the regulation of embryonic development, cell proliferation, survival and chemotaxis. Depending on the context, promotes or inhibits cell proliferation and cell migration. Plays an important role in the differentiation of bone marrow-derived mesenchymal stem cells. Required for normal skeleton development and cephalic closure during embryonic development. Required for normal development of the mucosa lining the gastrointestinal tract, and for recruitment of mesenchymal cells and normal development of intestinal villi. Plays a role in cell migration and chemotaxis in wound healing. Plays a role in platelet activation, secretion of agonists from platelet granules, and in thrombin-induced platelet aggregation. Binding of its cognate ligands - homodimeric PDGFA, homodimeric PDGFB, heterodimers formed by PDGFA and PDGFB or homodimeric PDGFC -leads to the activation of several signaling cascades; the response depends on the nature of the bound ligand and is modulated by the formation of heterodimers between PDGFRA and PDGFRB. Phosphorylates PIK3R1, PLCG1, and PTPN11. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, mobilization of cytosolic Ca(2+) and the activation of protein kinase C. Phosphorylates PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, and thereby mediates activation of the AKT1 signaling pathway. Mediates activation of HRAS and of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3 and STAT5A and/or STAT5B. Receptor signaling is down-regulated by protein phosphatases that dephosphorylate the receptor and its down-stream effectors, and by rapid internalization of the activated receptor
- Specific Function
- Atp binding
- Gene Name
- PDGFRA
- Uniprot ID
- P16234
- Uniprot Name
- Platelet-derived growth factor receptor alpha
- Molecular Weight
- 122668.46 Da
References
- EMA Assessment Report: Fotivda (tivozanib) oral capsules [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- General Function
- Non-receptor tyrosine-protein kinase implicated in the regulation of a variety of signaling pathways that control the differentiation and maintenance of normal epithelia, as well as tumor growth. Function seems to be context dependent and differ depending on cell type, as well as its intracellular localization. A number of potential nuclear and cytoplasmic substrates have been identified. These include the RNA-binding proteins: KHDRBS1/SAM68, KHDRBS2/SLM1, KHDRBS3/SLM2 and SFPQ/PSF; transcription factors: STAT3 and STAT5A/B and a variety of signaling molecules: ARHGAP35/p190RhoGAP, PXN/paxillin, BTK/ATK, STAP2/BKS. Associates also with a variety of proteins that are likely upstream of PTK6 in various signaling pathways, or for which PTK6 may play an adapter-like role. These proteins include ADAM15, EGFR, ERBB2, ERBB3 and IRS4. In normal or non-tumorigenic tissues, PTK6 promotes cellular differentiation and apoptosis. In tumors PTK6 contributes to cancer progression by sensitizing cells to mitogenic signals and enhancing proliferation, anchorage-independent survival and migration/invasion. Association with EGFR, ERBB2, ERBB3 may contribute to mammary tumor development and growth through enhancement of EGF-induced signaling via BTK/AKT and PI3 kinase. Contributes to migration and proliferation by contributing to EGF-mediated phosphorylation of ARHGAP35/p190RhoGAP, which promotes association with RASA1/p120RasGAP, inactivating RhoA while activating RAS. EGF stimulation resulted in phosphorylation of PNX/Paxillin by PTK6 and activation of RAC1 via CRK/CrKII, thereby promoting migration and invasion. PTK6 activates STAT3 and STAT5B to promote proliferation. Nuclear PTK6 may be important for regulating growth in normal epithelia, while cytoplasmic PTK6 might activate oncogenic signaling pathways
- Specific Function
- Atp binding
- Gene Name
- PTK6
- Uniprot ID
- Q13882
- Uniprot Name
- Protein-tyrosine kinase 6
- Molecular Weight
- 51833.72 Da
References
- EMA Assessment Report: Fotivda (tivozanib) oral capsules [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- General Function
- Tyrosine-protein kinase that acts as a cell-surface receptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskeleton, but also maintenance of vascular quiescence. Has anti-inflammatory effects by preventing the leakage of pro-inflammatory plasma proteins and leukocytes from blood vessels. Required for normal angiogenesis and heart development during embryogenesis. Required for post-natal hematopoiesis. After birth, activates or inhibits angiogenesis, depending on the context. Inhibits angiogenesis and promotes vascular stability in quiescent vessels, where endothelial cells have tight contacts. In quiescent vessels, ANGPT1 oligomers recruit TEK to cell-cell contacts, forming complexes with TEK molecules from adjoining cells, and this leads to preferential activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascades. In migrating endothelial cells that lack cell-cell adhesions, ANGT1 recruits TEK to contacts with the extracellular matrix, leading to the formation of focal adhesion complexes, activation of PTK2/FAK and of the downstream kinases MAPK1/ERK2 and MAPK3/ERK1, and ultimately to the stimulation of sprouting angiogenesis. ANGPT1 signaling triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Signaling is modulated by ANGPT2 that has lower affinity for TEK, can promote TEK autophosphorylation in the absence of ANGPT1, but inhibits ANGPT1-mediated signaling by competing for the same binding site. Signaling is also modulated by formation of heterodimers with TIE1, and by proteolytic processing that gives rise to a soluble TEK extracellular domain. The soluble extracellular domain modulates signaling by functioning as decoy receptor for angiopoietins. TEK phosphorylates DOK2, GRB7, GRB14, PIK3R1; SHC1 and TIE1
- Specific Function
- Atp binding
- Gene Name
- TEK
- Uniprot ID
- Q02763
- Uniprot Name
- Angiopoietin-1 receptor
- Molecular Weight
- 125829.005 Da
References
- EMA Assessment Report: Fotivda (tivozanib) oral capsules [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration. Required for normal mesoderm patterning and correct axial organization during embryonic development, normal skeletogenesis and normal development of the gonadotropin-releasing hormone (GnRH) neuronal system. Phosphorylates PLCG1, FRS2, GAB1 and SHB. Ligand binding 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. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes phosphorylation of SHC1, STAT1 and PTPN11/SHP2. In the nucleus, enhances RPS6KA1 and CREB1 activity and contributes to the regulation of transcription. FGFR1 signaling is down-regulated by IL17RD/SEF, and by FGFR1 ubiquitination, internalization and degradation
- Specific Function
- Atp binding
- Gene Name
- FGFR1
- Uniprot ID
- P11362
- Uniprot Name
- Fibroblast growth factor receptor 1
- Molecular Weight
- 91866.935 Da
References
- EMA Assessment Report: Fotivda (tivozanib) oral capsules [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- 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
- EMA Assessment Report: Fotivda (tivozanib) oral capsules [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- 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
- Wang J, Bruin MAC, Gan C, Lebre MC, Rosing H, Beijnen JH, Schinkel AH: Brain accumulation of tivozanib is restricted by ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein) in mice. Int J Pharm. 2020 May 15;581:119277. doi: 10.1016/j.ijpharm.2020.119277. Epub 2020 Mar 28. [Article]
- FDA Approved Drug Products: FOTIVDA (tivozanib) capsules, for oral use [Link]
- EMC Summary of Product Characteristics: Fotivda (tivozanib hydrochloride monohydrate) oral capsules [Link]
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Binder
- General Function
- Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017)
- Specific Function
- Antioxidant activity
- Gene Name
- ALB
- Uniprot ID
- P02768
- Uniprot Name
- Albumin
- Molecular Weight
- 69365.94 Da
References
- FDA Approved Drug Products: FOTIVDA (tivozanib) capsules, for oral use [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- Curator comments
- Prescribing information indicates that tivozanib is not a substrate for P-glycoprotein, however an in vitro study shows that tivozanib is transported by P-glycoprotein. Clinical significance is unknown.
- General Function
- Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
- Specific Function
- Abc-type xenobiotic transporter activity
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- ATP-dependent translocase ABCB1
- Molecular Weight
- 141477.255 Da
References
- Wang J, Bruin MAC, Gan C, Lebre MC, Rosing H, Beijnen JH, Schinkel AH: Brain accumulation of tivozanib is restricted by ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein) in mice. Int J Pharm. 2020 May 15;581:119277. doi: 10.1016/j.ijpharm.2020.119277. Epub 2020 Mar 28. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- Curator comments
- Tivozanib inhibits BCRP in vitro, but this has not been proven in vivo. Clinical significance is unknown.
- General Function
- Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells (PubMed:11306452, PubMed:12958161, PubMed:19506252, PubMed:20705604, PubMed:28554189, PubMed:30405239, PubMed:31003562). Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme (PubMed:20705604, PubMed:23189181). Also mediates the efflux of sphingosine-1-P from cells (PubMed:20110355). Acts as a urate exporter functioning in both renal and extrarenal urate excretion (PubMed:19506252, PubMed:20368174, PubMed:22132962, PubMed:31003562, PubMed:36749388). In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate (By similarity). Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates (PubMed:12682043, PubMed:28554189, PubMed:30405239). Mediates the secretion of the riboflavin and biotin vitamins into milk (By similarity). Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability (By similarity). Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux (PubMed:11306452, PubMed:12477054, PubMed:15670731, PubMed:18056989, PubMed:31254042). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus (By similarity). May play a role in early stem cell self-renewal by blocking differentiation (By similarity)
- Specific Function
- Abc-type xenobiotic transporter activity
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- Broad substrate specificity ATP-binding cassette transporter ABCG2
- Molecular Weight
- 72313.47 Da
References
- Yang D, Kathawala RJ, Chufan EE, Patel A, Ambudkar SV, Chen ZS, Chen X: Tivozanib reverses multidrug resistance mediated by ABCB1 (P-glycoprotein) and ABCG2 (BCRP). Future Oncol. 2014 Aug;10(11):1827-41. doi: 10.2217/fon.13.253. Epub 2013 Dec 3. [Article]
- EMC Summary of Product Characteristics: Fotivda (tivozanib hydrochloride monohydrate) oral capsules [Link]
Drug created at October 20, 2016 20:49 / Updated at September 16, 2024 01:08