Identification

Name
Sunitinib
Accession Number
DB01268
Description

Sunitinib is a small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor. On January 26, 2006, the agent was formally approved by the US FDA for the indications of treating renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST). For these purposes, sunitinib is generally available as an orally administered formulation. Sunitinib inhibits cellular signaling by targeting multiple RTKs. These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R). Sunitinib also inhibits KIT (CD117), the RTK that drives the majority of GISTs. In addition, sunitinib inhibits other RTKs including RET, CSF-1R, and flt3.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 398.4738
Monoisotopic: 398.211804333
Chemical Formula
C22H27FN4O2
Synonyms
  • Sunitinib
  • Sunitinibum
External IDs
  • SU-011248
  • SU-11248
  • SU011248
  • SU11248

Pharmacology

Indication

For the treatment of advanced renal cell carcinoma as well as the treatment of gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate.

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
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Pharmacodynamics

Sunitinib is an oral, small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA on January 26, 2006.

Mechanism of action

Sunitinib is a small molecule that inhibits multiple RTKs, some of which are implicated in tumor growth, pathologic angiogenesis, and metastatic progression of cancer. Sunitinib was evaluated for its inhibitory activity against a variety of kinases (>80 kinases) and was identified as an inhibitor of platelet-derived growth factor receptors (PDGFRa and PDGFRb), vascular endothelial growth factor receptors (VEGFR1, VEGFR2 and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor Type 1 (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET). Sunitinib inhibition of the activity of these RTKs has been demonstrated in biochemical and cellular assays, and inhibition of function has been demonstrated in cell proliferation assays. The primary metabolite exhibits similar potency compared to sunitinib in biochemical and cellular assays.

TargetActionsOrganism
APlatelet-derived growth factor receptor beta
inhibitor
Humans
AVascular endothelial growth factor receptor 1
inhibitor
Humans
AMast/stem cell growth factor receptor Kit
inhibitor
Humans
AVascular endothelial growth factor receptor 2
inhibitor
Humans
AVascular endothelial growth factor receptor 3
inhibitor
Humans
AReceptor-type tyrosine-protein kinase FLT3
inhibitor
Humans
AMacrophage colony-stimulating factor 1 receptor
inhibitor
Humans
APlatelet-derived growth factor receptor alpha
inhibitor
Humans
Absorption

Maximum plasma concentrations (Cmax) of sunitinib are generally observed between 6 and 12 hours (Tmax) following oral administration. Food has no effect on the bioavailability of sunitinib. Sunitinib may be taken with or without food. The pharmacokinetics were similar in healthy volunteers and in the solid tumor patient populations tested, including patients with GIST and RCC.

Volume of distribution
  • 2230 L (apparent volume of distribution, Vd/F)
Protein binding

Binding of sunitinib and its primary metabolite to human plasma protein in vitro was 95% and 90%, respectively.

Metabolism

Sunitinib is metabolized primarily by the cytochrome P450 enzyme, CYP3A4, to produce its primary active metabolite, which is further metabolized by CYP3A4.

Route of elimination

Sunitinib is metabolized primarily by the cytochrome P450 enzyme, CYP3A4, to produce its primary active metabolite, which is further metabolized by CYP3A4. Elimination is primarily via feces. In a human mass balance study of [14C]sunitinib, 61% of the dose was eliminated in feces, with renal elimination accounting for 16% of the administered dose.

Half-life

Following administration of a single oral dose in healthy volunteers, the terminal half-lives of sunitinib and its primary active metabolite are approximately 40 to 60 hours and 80 to 110 hours, respectively.

Clearance
  • 34 - 62 L/h [Total oral clearance]
Adverse Effects
Learn about our commercial Adverse Effects data.
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Toxicity

The maximally tolerated dose for rat, mouse, and dog when given orally is greater than 500 mg/kg. The maximally tolerated dose of a non-human primate is greater 1200 mg/kg.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
Cytochrome P450 3A4---(A;A) / (A;G)G > AADR Directly StudiedPatients with metastatic renal cell carcinoma who carry this polymorphism in CYP3A4 are at a higher risk of experiencing drug-induced hypertension when treated with sunitinib.Details

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.
DrugInteraction
AbaloparatideThe therapeutic efficacy of Abaloparatide can be decreased when used in combination with Sunitinib.
AbametapirThe serum concentration of Sunitinib can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Sunitinib can be increased when combined with Abatacept.
AbemaciclibSunitinib may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
AbirateroneThe metabolism of Abiraterone can be decreased when combined with Sunitinib.
AcalabrutinibThe metabolism of Sunitinib can be decreased when combined with Acalabrutinib.
AcarboseThe risk or severity of hypoglycemia can be increased when Acarbose is combined with Sunitinib.
AcebutololThe therapeutic efficacy of Acebutolol can be increased when used in combination with Sunitinib.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Sunitinib.
AcetaminophenThe metabolism of Acetaminophen can be increased when combined with Sunitinib.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
  • Avoid grapefruit products. Grapefruit may reduce the CYP3A4 metabolism of sunitinib.
  • Avoid St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce the serum concentration of sunitinib.
  • Take with or without food.

Products

Product Ingredients
IngredientUNIICASInChI Key
Sunitinib malateLVX8N1UT73341031-54-7LBWFXVZLPYTWQI-IPOVEDGCSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
SutentCapsule12.5 mgOralPfizer Canada Ulc2006-06-22Not applicableCanada flag
SutentCapsule25 mgOralPfizer2006-07-19Not applicableEU flag
SutentCapsule25 mg/1OralPfizer Laboratories Div Pfizer Inc2006-01-26Not applicableUS flag
SutentCapsule50 mgOralPfizer Canada Ulc2006-06-22Not applicableCanada flag
SutentCapsule37.5 mgOralPfizer2006-07-19Not applicableEU flag
SutentCapsule37.5 mg/1OralPfizer Laboratories Div Pfizer Inc2014-07-12Not applicableUS flag
SutentCapsule25 mgOralPfizer2006-07-19Not applicableEU flag
SutentCapsule12.5 mgOralPfizer2006-07-19Not applicableEU flag
SutentCapsule12.5 mg/1OralPfizer Laboratories Div Pfizer Inc2006-01-26Not applicableUS flag
SutentCapsule25 mgOralPfizer Canada Ulc2006-06-22Not applicableCanada flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

ATC Codes
L01XE04 — Sunitinib
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as indolines. These are compounds containing an indole moiety, which consists of pyrrolidine ring fused to benzene to form 2,3-dihydroindole.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Indoles and derivatives
Sub Class
Indolines
Direct Parent
Indolines
Alternative Parents
Pyrrole carboxamides / Substituted pyrroles / Aryl fluorides / Benzenoids / Vinylogous amides / Heteroaromatic compounds / Trialkylamines / Secondary carboxylic acid amides / Amino acids and derivatives / Lactams
show 6 more
Substituents
Amine / Amino acid or derivatives / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Azacycle / Benzenoid / Carbonyl group / Carboxamide group / Carboxylic acid derivative
show 20 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
monocarboxylic acid amide, pyrroles (CHEBI:38940)

Chemical Identifiers

UNII
V99T50803M
CAS number
557795-19-4
InChI Key
WINHZLLDWRZWRT-ATVHPVEESA-N
InChI
InChI=1S/C22H27FN4O2/c1-5-27(6-2)10-9-24-22(29)20-13(3)19(25-14(20)4)12-17-16-11-15(23)7-8-18(16)26-21(17)28/h7-8,11-12,25H,5-6,9-10H2,1-4H3,(H,24,29)(H,26,28)/b17-12-
IUPAC Name
N-[2-(diethylamino)ethyl]-5-{[(3Z)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]methyl}-2,4-dimethyl-1H-pyrrole-3-carboxamide
SMILES
CCN(CC)CCNC(=O)C1=C(C)NC(\C=C2/C(=O)NC3=C2C=C(F)C=C3)=C1C

References

Synthesis Reference

Ettore BIGATTI, Augusto CANAVESI, Peter Lindsay MACDONALD, Francesca Scarpitta, "PROCESSES FOR PREPARING SUNITINIB AND SALTS THEREOF." U.S. Patent US20090247767, issued October 01, 2009.

US20090247767
General References
  1. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):115-24. [PubMed:17215529]
  2. Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, McArthur G, Judson IR, Heinrich MC, Morgan JA, Desai J, Fletcher CD, George S, Bello CL, Huang X, Baum CM, Casali PG: Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006 Oct 14;368(9544):1329-38. [PubMed:17046465]
Human Metabolome Database
HMDB0015397
KEGG Drug
D06402
PubChem Compound
5329102
PubChem Substance
46507140
ChemSpider
4486264
BindingDB
4814
RxNav
357977
ChEBI
38940
ChEMBL
CHEMBL535
ZINC
ZINC000003964325
Therapeutic Targets Database
DCL000646
PharmGKB
PA162372840
PDBe Ligand
B49
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Sunitinib
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
PDB Entries
2y7j / 3g0e / 3g0f / 3miy / 3ti1 / 4agd / 4ks8 / 4qmz / 6jok / 6m11
show 4 more
FDA label
Download (159 KB)
MSDS
Download (98.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingBasic ScienceClear-cell Metastatic Renal Cell Carcinoma1
4Active Not RecruitingOtherMetastatic Renal Cell Cancer1
4CompletedOtherWell-differentiated Pancreatic Neuroendocrine Tumor1
4CompletedTreatmentGastrointestinal Neoplasms, Gastrointestinal Stromal Tumors1
4CompletedTreatmentGastrointestinal Stroma Tumors / Non-Small Cell Lung Carcinoma (NSCLC) / Renal Cell Adenocarcinoma / Renal-cell Cancer1
4CompletedTreatmentRenal Cell Adenocarcinoma1
4RecruitingTreatmentRefractory Solid Tumors1
4TerminatedTreatmentMetastatic Renal Cell Carcinoma1
3Active Not RecruitingTreatmentAdvanced Renal Cell Carcinoma / Metastatic Renal Cell Carcinoma1
3Active Not RecruitingTreatmentCarcinoma NOS / Enzyme Inhibitors / Kidney Diseases / Neoplasms by Site / Neoplasms, Kidney / Protein Kinase Inhibitors / Renal Cell Adenocarcinoma / Urologic Neoplasms1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Pfizer Inc.
Dosage Forms
FormRouteStrength
Capsule
CapsuleOral12.5 mg
CapsuleOral12.5 mg/1
CapsuleOral25 mg
CapsuleOral25 mg/1
CapsuleOral37.5 mg
CapsuleOral37.5 mg/1
CapsuleOral50 mg
CapsuleOral50 mg/1
Capsule12.5 mg
Capsule25 mg
CapsuleOral
Capsule37.5 mg
Capsule50 mg
Capsule, coatedOral12.5 mg
Capsule, coatedOral25 mg
Capsule, coatedOral66.8 mg
Prices
Unit descriptionCostUnit
Sutent 50 mg capsule333.39USD capsule
Sutent 25 mg capsule187.28USD capsule
Sutent 12.5 mg capsule93.64USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
CA2395461No2010-05-252020-12-22Canada flag
CA2399358No2006-03-212021-02-15Canada flag
US6573293Yes2003-06-032021-08-15US flag
US7211600Yes2007-05-012021-06-22US flag
US7125905Yes2006-10-242021-08-15US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

    Learn more

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility>25 mg/mL over pH of 1.2 to 6.8FDA label
logP5.2 FDA label
pKa8.95 FDA label
Predicted Properties
PropertyValueSource
Water Solubility0.0308 mg/mLALOGPS
logP3.24ALOGPS
logP2.93ChemAxon
logS-4.1ALOGPS
pKa (Strongest Acidic)11.46ChemAxon
pKa (Strongest Basic)9.04ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area77.23 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity116.27 m3·mol-1ChemAxon
Polarizability44.32 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9938
Blood Brain Barrier+0.7993
Caco-2 permeable-0.5948
P-glycoprotein substrateSubstrate0.8648
P-glycoprotein inhibitor IInhibitor0.6809
P-glycoprotein inhibitor IINon-inhibitor0.5466
Renal organic cation transporterNon-inhibitor0.7385
CYP450 2C9 substrateNon-substrate0.8727
CYP450 2D6 substrateNon-substrate0.7716
CYP450 3A4 substrateSubstrate0.641
CYP450 1A2 substrateNon-inhibitor0.5626
CYP450 2C9 inhibitorNon-inhibitor0.6437
CYP450 2D6 inhibitorNon-inhibitor0.6846
CYP450 2C19 inhibitorNon-inhibitor0.6261
CYP450 3A4 inhibitorNon-inhibitor0.5991
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.7032
Ames testNon AMES toxic0.5699
CarcinogenicityNon-carcinogens0.784
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.6794 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8597
hERG inhibition (predictor II)Inhibitor0.8398
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Vascular endothelial growth factor binding
Specific Function
Tyrosine-protein kinase that acts as 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...
Gene Name
PDGFRB
Uniprot ID
P09619
Uniprot Name
Platelet-derived growth factor receptor beta
Molecular Weight
123966.895 Da
References
  1. Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ, Lee LB, Murray LJ, Carver J, Chan E, Moss KG, Haznedar JO, Sukbuntherng J, Blake RA, Sun L, Tang C, Miller T, Shirazian S, McMahon G, Cherrington JM: In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res. 2003 Jan;9(1):327-37. [PubMed:12538485]
  2. Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM: SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther. 2003 May;2(5):471-8. [PubMed:12748309]
  3. Baratte S, Sarati S, Frigerio E, James CA, Ye C, Zhang Q: Quantitation of SU1 1248, an oral multi-target tyrosine kinase inhibitor, and its metabolite in monkey tissues by liquid chromatograph with tandem mass spectrometry following semi-automated liquid-liquid extraction. J Chromatogr A. 2004 Jan 23;1024(1-2):87-94. [PubMed:14753710]
  4. Pietras K, Hanahan D: A multitargeted, metronomic, and maximum-tolerated dose "chemo-switch" regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J Clin Oncol. 2005 Feb 10;23(5):939-52. Epub 2004 Nov 22. [PubMed:15557593]
  5. Gollob JA: Sorafenib: scientific rationales for single-agent and combination therapy in clear-cell renal cell carcinoma. Clin Genitourin Cancer. 2005 Dec;4(3):167-74. [PubMed:16425993]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Vegf-b-activated receptor activity
Specific 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 ...
Gene Name
FLT1
Uniprot ID
P17948
Uniprot Name
Vascular endothelial growth factor receptor 1
Molecular Weight
150767.185 Da
References
  1. O'Farrell AM, Foran JM, Fiedler W, Serve H, Paquette RL, Cooper MA, Yuen HA, Louie SG, Kim H, Nicholas S, Heinrich MC, Berdel WE, Bello C, Jacobs M, Scigalla P, Manning WC, Kelsey S, Cherrington JM: An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients. Clin Cancer Res. 2003 Nov 15;9(15):5465-76. [PubMed:14654525]
  2. Roskoski R Jr: Sunitinib: a VEGF and PDGF receptor protein kinase and angiogenesis inhibitor. Biochem Biophys Res Commun. 2007 May 4;356(2):323-8. Epub 2007 Mar 7. [PubMed:17367763]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Transmembrane receptor protein tyrosine kinase activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell main...
Gene Name
KIT
Uniprot ID
P10721
Uniprot Name
Mast/stem cell growth factor receptor Kit
Molecular Weight
109863.655 Da
References
  1. Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM: SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther. 2003 May;2(5):471-8. [PubMed:12748309]
  2. Schueneman AJ, Himmelfarb E, Geng L, Tan J, Donnelly E, Mendel D, McMahon G, Hallahan DE: SU11248 maintenance therapy prevents tumor regrowth after fractionated irradiation of murine tumor models. Cancer Res. 2003 Jul 15;63(14):4009-16. [PubMed:12873999]
  3. Joensuu H: Second line therapies for the treatment of gastrointestinal stromal tumor. Curr Opin Oncol. 2007 Jul;19(4):353-8. [PubMed:17545799]
  4. Baratte S, Sarati S, Frigerio E, James CA, Ye C, Zhang Q: Quantitation of SU1 1248, an oral multi-target tyrosine kinase inhibitor, and its metabolite in monkey tissues by liquid chromatograph with tandem mass spectrometry following semi-automated liquid-liquid extraction. J Chromatogr A. 2004 Jan 23;1024(1-2):87-94. [PubMed:14753710]
  5. Roskoski R Jr: Sunitinib: a VEGF and PDGF receptor protein kinase and angiogenesis inhibitor. Biochem Biophys Res Commun. 2007 May 4;356(2):323-8. Epub 2007 Mar 7. [PubMed:17367763]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Vascular endothelial growth factor-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and ...
Gene Name
KDR
Uniprot ID
P35968
Uniprot Name
Vascular endothelial growth factor receptor 2
Molecular Weight
151525.555 Da
References
  1. Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ, Lee LB, Murray LJ, Carver J, Chan E, Moss KG, Haznedar JO, Sukbuntherng J, Blake RA, Sun L, Tang C, Miller T, Shirazian S, McMahon G, Cherrington JM: In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res. 2003 Jan;9(1):327-37. [PubMed:12538485]
  2. Schueneman AJ, Himmelfarb E, Geng L, Tan J, Donnelly E, Mendel D, McMahon G, Hallahan DE: SU11248 maintenance therapy prevents tumor regrowth after fractionated irradiation of murine tumor models. Cancer Res. 2003 Jul 15;63(14):4009-16. [PubMed:12873999]
  3. Baratte S, Sarati S, Frigerio E, James CA, Ye C, Zhang Q: Quantitation of SU1 1248, an oral multi-target tyrosine kinase inhibitor, and its metabolite in monkey tissues by liquid chromatograph with tandem mass spectrometry following semi-automated liquid-liquid extraction. J Chromatogr A. 2004 Jan 23;1024(1-2):87-94. [PubMed:14753710]
  4. Schoffski P, Dumez H, Clement P, Hoeben A, Prenen H, Wolter P, Joniau S, Roskams T, Van Poppel H: Emerging role of tyrosine kinase inhibitors in the treatment of advanced renal cell cancer: a review. Ann Oncol. 2006 Aug;17(8):1185-96. Epub 2006 Jan 17. [PubMed:16418310]
  5. Amino N, Ideyama Y, Yamano M, Kuromitsu S, Tajinda K, Samizu K, Hisamichi H, Matsuhisa A, Shirasuna K, Kudoh M, Shibasaki M: YM-359445, an orally bioavailable vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor, has highly potent antitumor activity against established tumors. Clin Cancer Res. 2006 Mar 1;12(5):1630-8. [PubMed:16533791]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Vascular endothelial growth factor-activated receptor activity
Specific 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 cardi...
Gene Name
FLT4
Uniprot ID
P35916
Uniprot Name
Vascular endothelial growth factor receptor 3
Molecular Weight
152755.94 Da
References
  1. Roskoski R Jr: Sunitinib: a VEGF and PDGF receptor protein kinase and angiogenesis inhibitor. Biochem Biophys Res Commun. 2007 May 4;356(2):323-8. Epub 2007 Mar 7. [PubMed:17367763]
  2. Deprimo SE, Bello CL, Smeraglia J, Baum CM, Spinella D, Rini BI, Michaelson MD, Motzer RJ: Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins. J Transl Med. 2007 Jul 2;5:32. [PubMed:17605814]
  3. Katoh Y, Katoh M: Comparative integromics on VEGF family members. Int J Oncol. 2006 Jun;28(6):1585-9. [PubMed:16685460]
  4. Gridelli C, Maione P, Del Gaizo F, Colantuoni G, Guerriero C, Ferrara C, Nicolella D, Comunale D, De Vita A, Rossi A: Sorafenib and sunitinib in the treatment of advanced non-small cell lung cancer. Oncologist. 2007 Feb;12(2):191-200. [PubMed:17296815]
  5. Ahmed SI, Thomas AL, Steward WP: Vascular endothelial growth factor (VEGF) inhibition by small molecules. J Chemother. 2004 Nov;16 Suppl 4:59-63. [PubMed:15688612]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Vascular endothelial growth factor-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells...
Gene Name
FLT3
Uniprot ID
P36888
Uniprot Name
Receptor-type tyrosine-protein kinase FLT3
Molecular Weight
112902.51 Da
References
  1. O'Farrell AM, Abrams TJ, Yuen HA, Ngai TJ, Louie SG, Yee KW, Wong LM, Hong W, Lee LB, Town A, Smolich BD, Manning WC, Murray LJ, Heinrich MC, Cherrington JM: SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood. 2003 May 1;101(9):3597-605. Epub 2003 Jan 16. [PubMed:12531805]
  2. O'Farrell AM, Foran JM, Fiedler W, Serve H, Paquette RL, Cooper MA, Yuen HA, Louie SG, Kim H, Nicholas S, Heinrich MC, Berdel WE, Bello C, Jacobs M, Scigalla P, Manning WC, Kelsey S, Cherrington JM: An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients. Clin Cancer Res. 2003 Nov 15;9(15):5465-76. [PubMed:14654525]
  3. Baratte S, Sarati S, Frigerio E, James CA, Ye C, Zhang Q: Quantitation of SU1 1248, an oral multi-target tyrosine kinase inhibitor, and its metabolite in monkey tissues by liquid chromatograph with tandem mass spectrometry following semi-automated liquid-liquid extraction. J Chromatogr A. 2004 Jan 23;1024(1-2):87-94. [PubMed:14753710]
  4. Schmidt-Arras D, Schwable J, Bohmer FD, Serve H: Flt3 receptor tyrosine kinase as a drug target in leukemia. Curr Pharm Des. 2004;10(16):1867-83. [PubMed:15180525]
  5. Yee KW, Schittenhelm M, O'Farrell AM, Town AR, McGreevey L, Bainbridge T, Cherrington JM, Heinrich MC: Synergistic effect of SU11248 with cytarabine or daunorubicin on FLT3 ITD-positive leukemic cells. Blood. 2004 Dec 15;104(13):4202-9. Epub 2004 Aug 10. [PubMed:15304385]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Protein homodimerization activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor ...
Gene Name
CSF1R
Uniprot ID
P07333
Uniprot Name
Macrophage colony-stimulating factor 1 receptor
Molecular Weight
107982.955 Da
References
  1. Guo J, Marcotte PA, McCall JO, Dai Y, Pease LJ, Michaelides MR, Davidsen SK, Glaser KB: Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors. Mol Cancer Ther. 2006 Apr;5(4):1007-13. [PubMed:16648572]
  2. Roskoski R Jr: Sunitinib: a VEGF and PDGF receptor protein kinase and angiogenesis inhibitor. Biochem Biophys Res Commun. 2007 May 4;356(2):323-8. Epub 2007 Mar 7. [PubMed:17367763]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Vascular endothelial growth factor-activated receptor activity
Specific 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 chem...
Gene Name
PDGFRA
Uniprot ID
P16234
Uniprot Name
Platelet-derived growth factor receptor alpha
Molecular Weight
122668.46 Da
References
  1. Prenen H, Cools J, Mentens N, Folens C, Sciot R, Schoffski P, Van Oosterom A, Marynen P, Debiec-Rychter M: Efficacy of the kinase inhibitor SU11248 against gastrointestinal stromal tumor mutants refractory to imatinib mesylate. Clin Cancer Res. 2006 Apr 15;12(8):2622-7. [PubMed:16638875]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Flockhart Table of Drug Interactions [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A7
Uniprot ID
P24462
Uniprot Name
Cytochrome P450 3A7
Molecular Weight
57525.03 Da
References
  1. Flockhart Table of Drug Interactions [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Filppula AM, Neuvonen PJ, Backman JT: In vitro assessment of time-dependent inhibitory effects on CYP2C8 and CYP3A activity by fourteen protein kinase inhibitors. Drug Metab Dispos. 2014 Jul;42(7):1202-9. doi: 10.1124/dmd.114.057695. Epub 2014 Apr 8. [PubMed:24713129]
  2. Flockhart Table of Drug Interactions [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Atpase activity, coupled to transmembrane movement of substances
Specific Function
May be an organic anion pump relevant to cellular detoxification.
Gene Name
ABCC4
Uniprot ID
O15439
Uniprot Name
Multidrug resistance-associated protein 4
Molecular Weight
149525.33 Da
References
  1. Hu S, Chen Z, Franke R, Orwick S, Zhao M, Rudek MA, Sparreboom A, Baker SD: Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters. Clin Cancer Res. 2009 Oct 1;15(19):6062-9. doi: 10.1158/1078-0432.CCR-09-0048. Epub 2009 Sep 22. [PubMed:19773380]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Hu S, Chen Z, Franke R, Orwick S, Zhao M, Rudek MA, Sparreboom A, Baker SD: Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters. Clin Cancer Res. 2009 Oct 1;15(19):6062-9. doi: 10.1158/1078-0432.CCR-09-0048. Epub 2009 Sep 22. [PubMed:19773380]
  2. Shukla S, Robey RW, Bates SE, Ambudkar SV: Sunitinib (Sutent, SU11248), a small-molecule receptor tyrosine kinase inhibitor, blocks function of the ATP-binding cassette (ABC) transporters P-glycoprotein (ABCB1) and ABCG2. Drug Metab Dispos. 2009 Feb;37(2):359-65. doi: 10.1124/dmd.108.024612. Epub 2008 Oct 29. [PubMed:18971320]
  3. Tang SC, Lagas JS, Lankheet NA, Poller B, Hillebrand MJ, Rosing H, Beijnen JH, Schinkel AH: Brain accumulation of sunitinib is restricted by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and can be enhanced by oral elacridar and sunitinib coadministration. Int J Cancer. 2012 Jan 1;130(1):223-33. doi: 10.1002/ijc.26000. Epub 2011 Apr 7. [PubMed:21351087]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Organic anion transmembrane transporter activity
Specific Function
Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter.
Gene Name
ABCC2
Uniprot ID
Q92887
Uniprot Name
Canalicular multispecific organic anion transporter 1
Molecular Weight
174205.64 Da
References
  1. Hu S, Chen Z, Franke R, Orwick S, Zhao M, Rudek MA, Sparreboom A, Baker SD: Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters. Clin Cancer Res. 2009 Oct 1;15(19):6062-9. doi: 10.1158/1078-0432.CCR-09-0048. Epub 2009 Sep 22. [PubMed:19773380]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. Hu S, Chen Z, Franke R, Orwick S, Zhao M, Rudek MA, Sparreboom A, Baker SD: Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters. Clin Cancer Res. 2009 Oct 1;15(19):6062-9. doi: 10.1158/1078-0432.CCR-09-0048. Epub 2009 Sep 22. [PubMed:19773380]
  2. Dai CL, Liang YJ, Wang YS, Tiwari AK, Yan YY, Wang F, Chen ZS, Tong XZ, Fu LW: Sensitization of ABCG2-overexpressing cells to conventional chemotherapeutic agent by sunitinib was associated with inhibiting the function of ABCG2. Cancer Lett. 2009 Jun 28;279(1):74-83. doi: 10.1016/j.canlet.2009.01.027. Epub 2009 Feb 18. [PubMed:19232821]
  3. Shukla S, Robey RW, Bates SE, Ambudkar SV: Sunitinib (Sutent, SU11248), a small-molecule receptor tyrosine kinase inhibitor, blocks function of the ATP-binding cassette (ABC) transporters P-glycoprotein (ABCB1) and ABCG2. Drug Metab Dispos. 2009 Feb;37(2):359-65. doi: 10.1124/dmd.108.024612. Epub 2008 Oct 29. [PubMed:18971320]

Drug created on May 16, 2007 14:11 / Updated on October 21, 2020 01:55

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