vandetanib   Click here for help

GtoPdb Ligand ID: 5717

Synonyms: Caprelsa® | CH 331 | ZD 6474 | ZD-6474 | ZD6474
Approved drug PDB Ligand
vandetanib is an approved drug (FDA (2011), EMA (2012))
Compound class: Synthetic organic
Comment: Vandetanib is a Type-1 kinase inhibitor. It potently inhibits RET, VEGFR-2 (KDR) and EGFR tyrosine kinase activity [2].
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 4
Hydrogen bond donors 1
Rotatable bonds 6
Topological polar surface area 59.51
Molecular weight 474.11
XLogP 4.14
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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Canonical SMILES COc1cc2c(ncnc2cc1OCC1CCN(CC1)C)Nc1ccc(cc1F)Br
Isomeric SMILES COc1cc2c(ncnc2cc1OCC1CCN(CC1)C)Nc1ccc(cc1F)Br
InChI InChI=1S/C22H24BrFN4O2/c1-28-7-5-14(6-8-28)12-30-21-11-19-16(10-20(21)29-2)22(26-13-25-19)27-18-4-3-15(23)9-17(18)24/h3-4,9-11,13-14H,5-8,12H2,1-2H3,(H,25,26,27)
InChI Key UHTHHESEBZOYNR-UHFFFAOYSA-N
No information available.
Summary of Clinical Use Click here for help
Used in the treatment of thyroid cancer.
Mechanism Of Action and Pharmacodynamic Effects Click here for help
VEGFR- and EGFR-dependent signalling pathways have been shown to be involved in some types of cancer, including non-small-cell lung cancer (NSCLC) and RET activity is important in some types of thyroid cancer. Vandetanib potently inhibits VEGFR-2, EGFR and RET tyrosine kinases. It is also a sub-micromolar inhibitor of VEGFR-3 tyrosine kinase.
Pharmacokinetics Click here for help
Absorption/Distribution
Vandatenib is absorbed slowly, taking 4-10h to reach peak plasma concentration. Protein binding (albumin and α-1 acid glycoprotein) is approximately 90%. Volume of distributuion is >7L suggesting extensive distribution from the plasma into tissues.
Biotransformation/Metabolism
CYP3A4 metabilizes vandatenib to N-desmethyl-vandetanib and the flavin-containing monooxygenase enzymes (FMO1 and FMO3) convert the parent drug to vandetanib-N-oxide. Unchanged vandentanib and its metabolites can be detected in plasma, urine and feces.
Elimination
Vandatenib is eliminated primarily in the feces (44%) and the urine (25%).
Population pharmacokinetics
Pharmacokinetics of vandatenib are not significantly affected by age or gender. The pharmacokinetics have not been evaluated in children. Japanese and Chinese patients had, on average, exposures that were higher than in white patients receiving the same dose.
Organ function impairment
Hepatic impairment: A single dose pharmacokinetic study in volunteers indicated that hepatic impairment did not affect exposure to vandetanib. However, vanatenib treatment is not recommended for use in patients with moderate and severe hepatic impairment because safety and efficacy are not well established. Renal impairment: A single dose pharmacokinetic study in volunteers indicated that exposure to vandetanib is enhanced (up to 1.5, 1.6 and 2-fold) in mild, moderate and severe renal impaired subjects respectively, compared to subjects with normal renal function.
External links Click here for help
For extended ADME data see the following:

Electronic Medicines Compendium (eMC)
Drugs.com
European Medicines Agency (EMA)