vandetanib 🐶 Veterinary Use | Indications/Contra | FAERs-F | FAERs-M | Orange Bk | PK/Tox | Related Drugs | BioActivity |

Stem definitionDrug idCAS RN
angiogenesis inhibitors 4178 443913-73-3

Description:

MoleculeDescription

Molfile Inchi Smiles

Synonyms:

  • ZD-6474
  • vandetanib
  • zactima
  • caprelsa
  • ZD6474
In vitro studies have shown that vandetanib inhibits the tyrosine kinase activity of the EGFR and VEGFR families, RET, BRK, TIE2, and members of the EPH receptor and Src kinase families. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment. In addition, the N-desmethyl metabolite of the drug, representing 7 to 17.1% of vandetanib exposure, has similar inhibitory activity to the parent compound for VEGF receptors (KDR and Flt-1) and EGFR. In vitro, vandetanib inhibited epidermal growth factor (EGF)-stimulated receptor tyrosine kinase phosphorylation in tumor cells and endothelial cells and VEGF-stimulated tyrosine kinase phosphorylation in endothelial cells. In vivo, vandetanib administration reduced tumor cell-induced angiogenesis, tumor vessel permeability, and inhibited tumor growth and metastasis in mouse models of cancer.
  • Molecular weight: 475.36
  • Formula: C22H24BrFN4O2
  • CLOGP: 5.69
  • LIPINSKI: 1
  • HAC: 6
  • HDO: 1
  • TPSA: 59.51
  • ALOGS: -4.67
  • ROTB: 6
  • Status: OFP
    • Legend:
    OFP - off patent
    OFM - off market
    ONP - on patent

Drug dosage:

DoseUnitRoute
0.30 g O

ADMET properties:

PropertyValueReference
BDDCS (Biopharmaceutical Drug Disposition Classification System) 2 Hosey CM, Chan R, Benet LZ
S (Water solubility) 0.01 mg/mL Bocci G, Oprea TI, Benet LZ
BA (Bioavailability) 21.40 %

Predicted pharmacokinetic/toxicological properties (PK-AZ):

PropertyDescriptionValueUnitConfidenceSimilarity
azlogd74 LogD at pH 7.4 2.711 High 1
caco2-efflux Caco-2 efflux ratio (BA/AB) 0.982 High 1
caco2-intrinsic-papp Caco-2 intrinsic apparent permeability 21.928 10^-6 cm/s High 1
dh-clint Dog hepatocyte intrinsic clearance 22.029 uL/min/10^6 cells High 1
dppb Dog plasma protein binding (% unbound) 12.430 % High 1
fcs-ppb Fetal calf serum protein binding (% unbound) 27.130 % High 1
herg hERG pIC50 6.145 pIC50 High 1
hh-clint Human hepatocyte intrinsic clearance 2.004 uL/min/10^6 cells High 1
hlm-clint Human liver microsomal intrinsic clearance 7.079 uL/min/mg protein High 1
hppb Human plasma protein binding (% unbound) 10.320 % High 1
kinase-safety-class ABL1,ABL2,ACVR2A,ACVR2B,ACVRL1,AKT1,AKT2,AKT3,ALK,AURKA,AURKB,AURKC,AXL,BLK,BMX,BRAF,BTK,CAMK2B,CAMK2D,CAMK2G,CDK5,CDK9,CHEK1,CSF1R,CSK,DDR1,DYRK1B,EGFR,EIF2AK3,EPHA2,EPHB1,EPHB4,ERBB2,ERBB4,FGFR1,FLT1,FLT3,FLT4,FYN,GAK,GRK2,GSK3B,INSR,IRAK1,IRAK3,IRAK4,ITK,JAK1,JAK2,KDR,KIT,LCK,LYN,MAP2K1,MAP3K1,MAP3K10,MAP3K14,MAP3K21,MAP3K7,MAP4K1,MAP4K2,MAP4K3,MAP4K5,MAPK10,MAPK11,MAPK12,MAPK14,MAPK7,MAPKAPK2,MARK4,MELK,MET,MINK1,MKNK1,MKNK2,MTOR,NTRK1,NTRK2,PAK4,PDGFRB,PDK1,PDK2,PDK4,PDPK1,PIK3CD,PRKCD,PRKDC,PTK6,RET,RIPK3,SIK2,SIK3,SRC,STK33,SYK,TEK,TGFBR1,TNIK,TTK,TYRO3,ULK1,YES1 102
kinase-selectivity-class ACVR2B,ALK,AURKA,AXL,BLK,BRAF,CAMK2D,CDK9,CSF1R,CSK,DDR1,DYRK1B,EGFR,EPHA2,EPHB4,ERBB2,ERBB4,FLT1,FLT3,FYN,IRAK1,IRAK4,JAK1,KDR,KIT,LCK,LYN,MAP3K1,MAP3K21,MAP4K1,MAP4K3,MAPK7,MET,MKNK1,PAK4,PDK4,PRKCD,RET,SIK2,SIK3,SRC,STK33,SYK,TEK,ULK1,YES1 46
mdck-mdr1-efflux MDCK-MDR1 efflux ratio 5.458 High 1
mh-clint Mouse hepatocyte intrinsic clearance 11.272 High 1
mppb Mouse plasma protein binding (% unbound) 9.110 High 1
nih-mdck-mdr1-efflux NIH MDCK-MDR1 efflux ratio 14.962 High 1
pfas-class PFAS structural alert (1 = True, 0 = False) 0
pppb Pig plasma protein binding (% unbound) 21.750 % High 1
rh-clint Rat hepatocyte intrinsic clearance 7.638 uL/min/10^6 cells High 1
rh-fuinc Rat hepatocyte fraction unbound in incubation 21.710 % High 1
rppb Rat plasma protein binding (% unbound) 9.660 % High 1
solubility-dd Solubility at pH 7.4 in DMSO 587.489 uM High 1

Approvals:

DateAgencyCompanyOrphan
April 6, 2011 FDA IPR PHARMS INC
Feb. 16, 2012 EMA GENZYME EUROPE BV

FDA Adverse Event Reporting System (Female)

MedDRA adverse event termLikelihood ratioLikelihood ratio thresholdPatients taking drug having adverse eventPatients taking drug not having adverse eventPatients not taking drug having adverse eventPatients not taking drug not having adverse event
Electrocardiogram QT prolonged 159.02 33.03 57 1620 72399 90554371
Reflux gastritis 86.87 33.03 16 1661 1388 90625382
Hypophosphataemia 66.14 33.03 20 1657 14834 90611936
Facial paralysis 65.25 33.03 20 1657 15514 90611256
Lymphocyte count decreased 63.48 33.03 24 1653 35026 90591744
Blood triglycerides increased 63.30 33.03 19 1658 13742 90613028
Ataxia 62.31 33.03 20 1657 18022 90608748
Myoclonus 61.12 33.03 20 1657 19148 90607622
Metastases to liver 56.81 33.03 21 1656 28786 90597984
Hypophagia 55.78 33.03 22 1655 35915 90590855
Metastases to bone 55.52 33.03 20 1657 25485 90601285
Metastases to central nervous system 54.70 33.03 18 1659 17524 90609246
Hemiparesis 51.21 33.03 20 1657 31799 90594971
Ocular hyperaemia 50.04 33.03 20 1657 33778 90592992
Flatulence 49.44 33.03 21 1656 41346 90585424
Malignant neoplasm progression 45.74 33.03 27 1650 106843 90519927
Neutrophil count decreased 44.13 33.03 23 1654 71509 90555261
Disease progression 43.23 33.03 30 1647 156585 90470185
Diarrhoea 42.93 33.03 68 1609 939122 89687648
Alanine aminotransferase increased 35.80 33.03 24 1653 118314 90508456
Abdominal distension 33.65 33.03 24 1653 130577 90496193
Pancytopenia 33.07 33.03 23 1654 120240 90506530

FDA Adverse Event Reporting System (Male)

MedDRA adverse event termLikelihood ratioLikelihood ratio thresholdPatients taking drug having adverse eventPatients taking drug not having adverse eventPatients not taking drug having adverse eventPatients not taking drug not having adverse event
Electrocardiogram QT prolonged 78.40 32.56 30 724 47915 42572666
Blood calcitonin increased 70.15 32.56 8 746 18 42620563
Diarrhoea 51.92 32.56 51 703 460798 42159783
Acne 47.33 32.56 15 739 13629 42606952
Photosensitivity reaction 36.05 32.56 12 742 12690 42607891

FDA Adverse Event Reporting System (Geriatric)

MedDRA adverse event termLikelihood ratioLikelihood ratio thresholdPatients taking drug having adverse eventPatients taking drug not having adverse eventPatients not taking drug having adverse eventPatients not taking drug not having adverse event
Electrocardiogram QT prolonged 180.32 29.68 72 2229 108888 110478110
Reflux gastritis 83.96 29.68 16 2285 1480 110585518
Blood calcitonin increased 71.59 29.68 9 2292 47 110586951
Diarrhoea 68.93 29.68 100 2201 1139405 109447593
Metastases to liver 60.48 29.68 24 2277 35362 110551636
Metastases to bone 59.69 29.68 23 2278 31349 110555649
Myoclonus 55.06 29.68 22 2279 32976 110554022
Facial paralysis 54.21 29.68 20 2281 24194 110562804
Hypertension 53.34 29.68 59 2242 510025 110076973
Flatulence 51.51 29.68 24 2277 52125 110534873
Acne 51.29 29.68 21 2280 33499 110553499
Blood triglycerides increased 50.77 29.68 19 2282 23907 110563091
Malignant neoplasm progression 50.43 29.68 36 2265 174531 110412467
Ataxia 49.98 29.68 20 2281 30088 110556910
Lymphocyte count decreased 49.38 29.68 24 2277 57219 110529779
Hypophosphataemia 48.10 29.68 20 2281 33162 110553836
Metastases to central nervous system 47.98 29.68 18 2283 22799 110564199
Hypophagia 45.20 29.68 22 2279 52604 110534394
Ocular hyperaemia 44.84 29.68 20 2281 39266 110547732
Hemiparesis 42.72 29.68 20 2281 43883 110543115
Blood calcitonin decreased 39.13 29.68 4 2297 0 110586998
Photosensitivity reaction 35.65 29.68 15 2286 25574 110561424
Neutrophil count decreased 30.50 29.68 23 2278 120918 110466080
Disease progression 30.31 29.68 31 2270 244003 110342995
Blood creatinine increased 29.83 29.68 27 2274 182862 110404136

FDA Adverse Event Reporting System (Pediatric)

None

Pharmacologic Action:

SourceCodeDescription
ATC L01EX04 ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
ANTINEOPLASTIC AGENTS
PROTEIN KINASE INHIBITORS
Other protein kinase inhibitors
FDA MoA N0000175076 Protein Kinase Inhibitors
FDA EPC N0000175605 Kinase Inhibitor
FDA MoA N0000185503 P-Glycoprotein Inhibitors
FDA MoA N0000187061 Organic Cation Transporter 2 Inhibitors
CHEBI has role CHEBI:35610 antineoplastic agent
CHEBI has role CHEBI:38637 tyrosine kinase inhibitor

Related Drugs by ATC class:

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Drug Use | Suggest Off label Use Form| |View source of the data|

DiseaseRelationSNOMED_IDDOID
Medullary thyroid carcinoma indication 255032005 DOID:3973
Carcinoma of thyroid indication 448216007
Hypocalcemia contraindication 5291005
Torsades de pointes contraindication 31722008
Hypertensive disorder contraindication 38341003 DOID:10763
Hypothyroidism contraindication 40930008 DOID:1459
Hypokalemia contraindication 43339004
Heart failure contraindication 84114007 DOID:6000
Prolonged QT interval contraindication 111975006
Hypomagnesemia contraindication 190855004
Impaired renal function disorder contraindication 197663003
Interstitial lung disease contraindication 233703007 DOID:3082
Cerebral ischemia contraindication 287731003
Pregnancy, function contraindication 289908002
Severe diarrhea contraindication 409587002
Breastfeeding (mother) contraindication 413712001
Congenital long QT syndrome contraindication 442917000
Posterior reversible encephalopathy syndrome contraindication 450886002
Significant Bleeding contraindication




🐶 Veterinary Drug Use

None

🐶 Veterinary products

None

Acid dissociation constants calculated using MoKa v3.0.0

Dissociation levelDissociation constantType (acidic/basic)
pKa1 9.58 Basic
pKa2 5.88 Basic

Orange Book patent data (new drug applications)

None

Orange Book exclusivity data (new drug applications)

None

Bioactivity Summary:

TargetClassPharosUniProtActionTypeActivity value
(-log[M])		Mechanism
action		Bioact sourceMoA source
Proto-oncogene tyrosine-protein kinase receptor Ret Kinase INHIBITOR Kd 7.85 CHEMBL CHEMBL
Epidermal growth factor receptor Kinase INHIBITOR Kd 8.32 CHEMBL CHEMBL
Vascular endothelial growth factor receptor 2 Kinase INHIBITOR Kd 6.33 CHEMBL CHEMBL
Tyrosine-protein kinase ABL1 Kinase Kd 8.05 CHEMBL
Mast/stem cell growth factor receptor Kit Kinase Kd 7.47 CHEMBL
Breakpoint cluster region protein Kinase Kd 6.06 CHEMBL
Proto-oncogene tyrosine-protein kinase Src Kinase INHIBITOR Kd 7.15 CHEMBL
Tyrosine-protein kinase Lck Kinase Kd 7.77 CHEMBL
Tyrosine-protein kinase Yes Kinase Kd 6.92 CHEMBL
Tyrosine-protein kinase Fyn Kinase Kd 6.44 CHEMBL
Ephrin type-A receptor 2 Kinase INHIBITOR Kd 5.96 CHEMBL
Receptor-type tyrosine-protein kinase FLT3 Kinase Kd 6.72 CHEMBL
Vascular endothelial growth factor receptor 1 Kinase INHIBITOR Kd 6.59 CHEMBL
Vascular endothelial growth factor receptor 3 Kinase INHIBITOR Kd 6.52 CHEMBL
Macrophage colony-stimulating factor 1 receptor Kinase Kd 5.92 CHEMBL
Platelet-derived growth factor receptor alpha Kinase Kd 6.64 CHEMBL
Receptor tyrosine-protein kinase erbB-2 Kinase INHIBITOR Kd 5.59 CHEMBL
Phosphorylase b kinase gamma catalytic chain, liver/testis isoform Kinase Kd 5.10 CHEMBL
Fibroblast growth factor receptor 3 Kinase Kd 6.62 CHEMBL
Tyrosine-protein kinase HCK Kinase Kd 6.44 CHEMBL
Receptor tyrosine-protein kinase erbB-4 Kinase INHIBITOR Kd 6.32 CHEMBL
Rho-associated protein kinase 2 Kinase Kd 5.44 CHEMBL
Tyrosine-protein kinase CSK Kinase Kd 5.60 CHEMBL
Angiopoietin-1 receptor Kinase INHIBITOR Kd 6 CHEMBL
Ephrin type-A receptor 8 Kinase INHIBITOR Kd 7.04 CHEMBL
Hepatocyte growth factor receptor Kinase Kd 5.39 CHEMBL
Tyrosine-protein kinase Lyn Kinase Kd 6.96 CHEMBL
5'-AMP-activated protein kinase catalytic subunit alpha-1 Kinase Kd 5.52 CHEMBL
Fibroblast growth factor receptor 1 Kinase Kd 6.25 CHEMBL
Phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform Kinase Kd 5.96 CHEMBL
Serine/threonine-protein kinase 10 Kinase Kd 7.09 CHEMBL
Serine/threonine-protein kinase PLK4 Kinase Kd 6.21 CHEMBL
Aurora kinase C Kinase Kd 5.82 CHEMBL
Abelson tyrosine-protein kinase 2 Kinase Kd 7.16 CHEMBL
Ephrin type-A receptor 5 Kinase INHIBITOR Kd 6.62 CHEMBL
Ephrin type-A receptor 4 Kinase INHIBITOR Kd 5.80 CHEMBL
Fibroblast growth factor receptor 2 Kinase Kd 5.96 CHEMBL
Ephrin type-A receptor 6 Kinase INHIBITOR Kd 7.30 CHEMBL
TRAF2 and NCK-interacting protein kinase Kinase Kd 5.64 CHEMBL
Casein kinase I isoform epsilon Kinase Kd 5.82 CHEMBL
Tyrosine-protein kinase Fgr Kinase Kd 6.57 CHEMBL
ALK tyrosine kinase receptor Kinase Kd 5.68 CHEMBL
Ephrin type-A receptor 3 Kinase INHIBITOR Kd 5.74 CHEMBL
Tyrosine-protein kinase FRK Kinase Kd 6.77 CHEMBL
Mitogen-activated protein kinase kinase kinase kinase 5 Kinase Kd 6.35 CHEMBL
Mitogen-activated protein kinase kinase kinase 4 Kinase Kd 5.52 CHEMBL
Cyclin-G-associated kinase Kinase Kd 7.07 CHEMBL
Receptor-interacting serine/threonine-protein kinase 2 Kinase Kd 8.34 CHEMBL
Ephrin type-B receptor 1 Kinase INHIBITOR Kd 6.54 CHEMBL
Ephrin type-A receptor 7 Kinase INHIBITOR Kd 5.62 CHEMBL
STE20-like serine/threonine-protein kinase Kinase Kd 7.02 CHEMBL
MAP kinase-interacting serine/threonine-protein kinase 2 Kinase Kd 5.77 CHEMBL
Epithelial discoidin domain-containing receptor 1 Kinase Kd 7.96 CHEMBL
Ephrin type-B receptor 4 Kinase INHIBITOR Kd 6.28 CHEMBL
Serine/threonine-protein kinase receptor R3 Kinase Kd 6.33 CHEMBL
Activin receptor type-1 Kinase Kd 6.82 CHEMBL
Dual specificity mitogen-activated protein kinase kinase 1 Kinase Kd 5.74 CHEMBL
Dual specificity mitogen-activated protein kinase kinase 2 Kinase Kd 5.96 CHEMBL
Protein-tyrosine kinase 6 Kinase INHIBITOR Kd 7.48 CHEMBL
Tyrosine-protein kinase BTK Kinase Kd 5.77 CHEMBL
Tyrosine-protein kinase receptor UFO Kinase Kd 6.60 CHEMBL
Tyrosine-protein kinase receptor TYRO3 Kinase Kd 7.03 CHEMBL
Ephrin type-B receptor 2 Kinase INHIBITOR Kd 6.36 CHEMBL
Cyclin-dependent kinase 7 Kinase Kd 5.39 CHEMBL
Ribosomal protein S6 kinase beta-1 Kinase Kd 5.80 CHEMBL
Ribosomal protein S6 kinase alpha-6 Kinase Kd 6.62 CHEMBL
Mitogen-activated protein kinase kinase kinase MLT Kinase Kd 5.29 CHEMBL
Tyrosine-protein kinase receptor Tie-1 Kinase Kd 5.82 CHEMBL
Tyrosine-protein kinase TXK Kinase Kd 5.43 CHEMBL
MAP kinase-interacting serine/threonine-protein kinase 1 Kinase Kd 6.44 CHEMBL
Serine/threonine-protein kinase SIK2 Kinase Kd 6.37 CHEMBL
Serine/threonine-protein kinase 33 Kinase Kd 5.85 CHEMBL
Serine/threonine-protein kinase TNNI3K Kinase Kd 5.55 CHEMBL
Discoidin domain-containing receptor 2 Kinase Kd 6.49 CHEMBL
Chaperone activity of bc1 complex-like, mitochondrial Kinase Kd 5.35 CHEMBL
Serine/threonine-protein kinase MRCK gamma Kinase Kd 5.66 CHEMBL
Leukocyte tyrosine kinase receptor Kinase Kd 6.26 CHEMBL
Mitogen-activated protein kinase kinase kinase kinase 1 Kinase Kd 5.26 CHEMBL
Mitogen-activated protein kinase kinase kinase kinase 3 Kinase Kd 5.82 CHEMBL
Tyrosine-protein kinase Blk Kinase Kd 7.18 CHEMBL
Mitogen-activated protein kinase kinase kinase kinase 4 Kinase Kd 5.85 CHEMBL
Tyrosine-protein kinase Mer Kinase Kd 5.85 CHEMBL
Serine/threonine-protein kinase MRCK alpha Kinase Kd 5.59 CHEMBL
Serine/threonine-protein kinase MRCK beta Kinase Kd 5.60 CHEMBL
Citron Rho-interacting kinase Kinase Kd 5.74 CHEMBL
AarF domain-containing protein kinase 4 Kinase Kd 5.77 CHEMBL
Serine/threonine-protein kinase SIK1 Kinase Kd 5.72 CHEMBL
Tyrosine-protein kinase Srms Kinase Kd 5.72 CHEMBL
Dual specificity testis-specific protein kinase 1 Kinase Kd 5.43 CHEMBL
Ephrin type-A receptor 1 Kinase INHIBITOR Kd 6.64 CHEMBL
Mitogen-activated protein kinase 6 Kinase Kd 5.82 CHEMBL
Fibroblast growth factor receptor 4 Kinase Kd 5.64 CHEMBL
Ribosomal protein S6 kinase alpha-1 Kinase Kd 6.40 CHEMBL
Mitogen-activated protein kinase kinase kinase kinase 2 Kinase Kd 5.80 CHEMBL
Misshapen-like kinase 1 Kinase Kd 5.47 CHEMBL
Interleukin-1 receptor-associated kinase 4 Kinase Kd 7.12 CHEMBL
Ephrin type-B receptor 6 Kinase INHIBITOR Kd 7.12 CHEMBL
Hormonally up-regulated neu tumor-associated kinase Kinase Kd 5.39 CHEMBL
Interleukin-1 receptor-associated kinase 1 Kinase Kd 5.92 CHEMBL
Serine/threonine-protein kinase ULK3 Kinase Kd 5.19 CHEMBL
Mitogen-activated protein kinase kinase kinase 19 Kinase Kd 6.01 CHEMBL
Receptor-interacting serine/threonine-protein kinase 4 Kinase Kd 6.21 CHEMBL
Serine/threonine-protein kinase 35 Kinase Kd 7.25 CHEMBL
Receptor tyrosine-protein kinase erbB-3 Kinase INHIBITOR Kd 6.80 CHEMBL
Serine/threonine-protein kinase SIK3 Kinase Kd 5.41 CHEMBL
Bone morphogenetic protein receptor type-1B Kinase Kd 6.62 CHEMBL
Serine/threonine-protein kinase 32A Kinase Kd 5.30 CHEMBL
Macrophage-stimulating protein receptor Kinase IC50 5.47 CHEMBL
Dual specificity mitogen-activated protein kinase kinase 5 Kinase Kd 7.31 CHEMBL
ATP-binding cassette sub-family G member 2 Transporter IC50 6.70 CHEMBL
Platelet-derived growth factor receptor beta Kinase Kd 7.06 CHEMBL
Tubulin alpha-1A chain Structural Kd 6.32 CHEMBL

External reference:

IDSource
4030726 VUID
N0000182736 NUI
D06407 KEGG_DRUG
4030726 VANDF
C1121849 UMLSCUI
CHEBI:49960 CHEBI
ZD6 PDB_CHEM_ID
CHEMBL24828 ChEMBL_ID
DB05294 DRUGBANK_ID
C452423 MESH_SUPPLEMENTAL_RECORD_UI
5717 IUPHAR_LIGAND_ID
8365 INN_ID
YO460OQ37K UNII
3081361 PUBCHEM_CID
1098413 RXNORM
181099 MMSL
189346 MMSL
27846 MMSL
d07761 MMSL
013703 NDDF
418260004 SNOMEDCT_US
418520004 SNOMEDCT_US
YO460OQ37K INXIGHT DRUGS

Pharmaceutical products:

ProductCategoryIngredientsNDCFormQuantityRouteMarketingLabel
CAPRELSA HUMAN PRESCRIPTION DRUG LABEL 1 58468-7820 TABLET, FILM COATED 100 mg ORAL NDA 33 sections
CAPRELSA HUMAN PRESCRIPTION DRUG LABEL 1 58468-7840 TABLET, FILM COATED 300 mg ORAL NDA 33 sections