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Identification
NameSunitinib
Accession NumberDB01268  (DB07417)
TypeSmall Molecule
GroupsApproved, Investigational
Description

Sunitinib is an oral, small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST) on January 26, 2006. 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.

Structure
Thumb
Synonyms
SU-11248
Sunitinib
Sunitinibum
Sutent
External Identifiers
  • SU011248
  • SU11248
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Sutentcapsule12.5 mg/1oralPfizer Laboratories Div Pfizer Inc2006-01-262016-04-23Us
Sutentcapsule37.5 mgoralPfizer Canada IncNot applicableNot applicableCanada
Sutentcapsule50 mgoralPfizer Canada Inc2006-06-22Not applicableCanada
Sutentcapsule25 mgoralPfizer Canada Inc2006-06-22Not applicableCanada
Sutentcapsule12.5 mgoralPfizer Canada Inc2006-06-22Not applicableCanada
Sutentcapsule50 mg/1oralPfizer Laboratories Div Pfizer Inc2006-01-262016-04-23Us
Sutentcapsule37.5 mg/1oralPfizer Laboratories Div Pfizer Inc2014-07-122016-04-23Us
Sutentcapsule25 mg/1oralPfizer Laboratories Div Pfizer Inc2006-01-262016-04-23Us
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International BrandsNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Sunitinib Malate
Thumb
  • InChI Key: LBWFXVZLPYTWQI-IPOVEDGCSA-N
  • Monoisotopic Mass: 532.233327635
  • Average Mass: 532.5612
DBSALT000166
Categories
UNIIV99T50803M
CAS number557795-19-4
WeightAverage: 398.4738
Monoisotopic: 398.211804333
Chemical FormulaC22H27FN4O2
InChI KeyInChIKey=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
Taxonomy
DescriptionThis 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.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassIndoles and derivatives
Sub ClassIndolines
Direct ParentIndolines
Alternative Parents
Substituents
  • Dihydroindole
  • Pyrrole-3-carboxylic acid or derivatives
  • Pyrrole-3-carboxamide
  • Fluorobenzene
  • Benzenoid
  • Substituted pyrrole
  • Aryl halide
  • Aryl fluoride
  • Heteroaromatic compound
  • Vinylogous amide
  • Pyrrole
  • Tertiary aliphatic amine
  • Tertiary amine
  • Secondary carboxylic acid amide
  • Lactam
  • Carboxamide group
  • Azacycle
  • Carboxylic acid derivative
  • Carboxylic acid amide
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Organofluoride
  • Organohalogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationFor 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.
PharmacodynamicsSunitinib is an oral, small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA on January 26, 2006.
Mechanism of actionSunitinib 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.
Related Articles
AbsorptionMaximum 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 bindingBinding 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 eliminationSunitinib 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 lifeFollowing 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]
ToxicityThe 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
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Capsuleoral12.5 mg/1
Capsuleoral12.5 mg
Capsuleoral25 mg
Capsuleoral25 mg/1
Capsuleoral37.5 mg
Capsuleoral37.5 mg/1
Capsuleoral50 mg/1
Capsuleoral50 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)
CA2395461 No2010-05-252020-12-22Canada
CA2399358 No2006-03-212021-02-15Canada
US6573293 No2001-02-152021-02-15Us
US7125905 No2001-02-152021-02-15Us
US7211600 No2000-12-222020-12-22Us
Properties
StateSolid
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 RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
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 ]
External Links
ATC CodesL01XE04
AHFS Codes
  • 92:00.00
PDB EntriesNot Available
FDA labelDownload (159 KB)
MSDSDownload (98.3 KB)
Interactions
Drug Interactions
Drug
AcetohexamideAcetohexamide may increase the hypoglycemic activities of Sunitinib.
Acetylsalicylic acidAcetylsalicylic acid may increase the hypoglycemic activities of Sunitinib.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Sunitinib.
AlogliptinAlogliptin may increase the hypoglycemic activities of Sunitinib.
AprepitantThe serum concentration of Sunitinib can be increased when it is combined with Aprepitant.
BevacizumabThe risk or severity of adverse effects can be increased when Sunitinib is combined with Bevacizumab.
BexaroteneThe serum concentration of Sunitinib can be decreased when it is combined with Bexarotene.
BosentanThe serum concentration of Sunitinib can be decreased when it is combined with Bosentan.
BosutinibThe serum concentration of Bosutinib can be increased when it is combined with Sunitinib.
Brentuximab vedotinThe serum concentration of Brentuximab vedotin can be increased when it is combined with Sunitinib.
CanagliflozinCanagliflozin may increase the hypoglycemic activities of Sunitinib.
CarbamazepineThe serum concentration of Sunitinib can be decreased when it is combined with Carbamazepine.
ChlorpropamideChlorpropamide may increase the hypoglycemic activities of Sunitinib.
CitalopramSunitinib may increase the QTc-prolonging activities of Citalopram.
ColchicineThe serum concentration of Colchicine can be increased when it is combined with Sunitinib.
ConivaptanThe serum concentration of Sunitinib can be increased when it is combined with Conivaptan.
Dabigatran etexilateThe serum concentration of the active metabolites of Dabigatran etexilate can be increased when Dabigatran etexilate is used in combination with Sunitinib.
DabrafenibThe serum concentration of Sunitinib can be decreased when it is combined with Dabrafenib.
DasatinibThe serum concentration of Sunitinib can be increased when it is combined with Dasatinib.
DeferasiroxThe serum concentration of Sunitinib can be decreased when it is combined with Deferasirox.
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Sunitinib.
DexamethasoneThe serum concentration of Sunitinib can be decreased when it is combined with Dexamethasone.
DihydrotestosteroneDihydrotestosterone may increase the hypoglycemic activities of Sunitinib.
DofetilideSunitinib may increase the QTc-prolonging activities of Dofetilide.
DoxorubicinThe serum concentration of Doxorubicin can be increased when it is combined with Sunitinib.
EdoxabanThe serum concentration of Edoxaban can be increased when it is combined with Sunitinib.
EnzalutamideThe serum concentration of Sunitinib can be decreased when it is combined with Enzalutamide.
EverolimusThe serum concentration of Everolimus can be increased when it is combined with Sunitinib.
FluconazoleThe metabolism of Sunitinib can be decreased when combined with Fluconazole.
FosaprepitantThe serum concentration of Sunitinib can be increased when it is combined with Fosaprepitant.
FosphenytoinThe serum concentration of Sunitinib can be decreased when it is combined with Fosphenytoin.
Fusidic AcidThe serum concentration of Sunitinib can be increased when it is combined with Fusidic Acid.
GliclazideGliclazide may increase the hypoglycemic activities of Sunitinib.
GlimepirideGlimepiride may increase the hypoglycemic activities of Sunitinib.
GliquidoneGliquidone may increase the hypoglycemic activities of Sunitinib.
GlyburideGlyburide may increase the hypoglycemic activities of Sunitinib.
GoserelinSunitinib may increase the QTc-prolonging activities of Goserelin.
IdelalisibThe serum concentration of Sunitinib can be increased when it is combined with Idelalisib.
Insulin AspartInsulin Aspart may increase the hypoglycemic activities of Sunitinib.
Insulin DetemirInsulin Detemir may increase the hypoglycemic activities of Sunitinib.
Insulin GlargineInsulin Glargine may increase the hypoglycemic activities of Sunitinib.
Insulin GlulisineInsulin Glulisine may increase the hypoglycemic activities of Sunitinib.
Insulin HumanInsulin Regular may increase the hypoglycemic activities of Sunitinib.
Insulin LisproInsulin Lispro may increase the hypoglycemic activities of Sunitinib.
ItraconazoleThe metabolism of Sunitinib can be decreased when combined with Itraconazole.
IvacaftorThe serum concentration of Sunitinib can be increased when it is combined with Ivacaftor.
KetoconazoleThe metabolism of Sunitinib can be decreased when combined with Ketoconazole.
LedipasvirThe serum concentration of Ledipasvir can be increased when it is combined with Sunitinib.
LeflunomideThe risk or severity of adverse effects can be increased when Sunitinib is combined with Leflunomide.
LeuprolideSunitinib may increase the QTc-prolonging activities of Leuprolide.
LinagliptinLinagliptin may increase the hypoglycemic activities of Sunitinib.
LuliconazoleThe serum concentration of Sunitinib can be increased when it is combined with Luliconazole.
MetforminMetformin may increase the hypoglycemic activities of Sunitinib.
MifepristoneThe serum concentration of Sunitinib can be increased when it is combined with Mifepristone.
MitotaneThe serum concentration of Sunitinib can be decreased when it is combined with Mitotane.
NaloxegolThe serum concentration of Naloxegol can be increased when it is combined with Sunitinib.
NatalizumabThe risk or severity of adverse effects can be increased when Sunitinib is combined with Natalizumab.
NelfinavirThe metabolism of Sunitinib can be decreased when combined with Nelfinavir.
NetupitantThe serum concentration of Sunitinib can be increased when it is combined with Netupitant.
OxandroloneOxandrolone may increase the hypoglycemic activities of Sunitinib.
PalbociclibThe serum concentration of Sunitinib can be increased when it is combined with Palbociclib.
PamidronateThe risk or severity of adverse effects can be increased when Sunitinib is combined with Pamidronate.
ParoxetineParoxetine may increase the hypoglycemic activities of Sunitinib.
PazopanibThe serum concentration of Pazopanib can be increased when it is combined with Sunitinib.
PegvisomantPegvisomant may increase the hypoglycemic activities of Sunitinib.
PhenelzinePhenelzine may increase the hypoglycemic activities of Sunitinib.
PhenobarbitalThe serum concentration of Sunitinib can be decreased when it is combined with Phenobarbital.
PhenytoinThe serum concentration of Sunitinib can be decreased when it is combined with Phenytoin.
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Sunitinib.
PosaconazoleThe metabolism of Sunitinib can be decreased when combined with Posaconazole.
PrimidoneThe serum concentration of Sunitinib can be decreased when it is combined with Primidone.
PrucaloprideThe serum concentration of Prucalopride can be increased when it is combined with Sunitinib.
RanolazineThe serum concentration of Ranolazine can be increased when it is combined with Sunitinib.
RepaglinideRepaglinide may increase the hypoglycemic activities of Sunitinib.
RifabutinThe serum concentration of Sunitinib can be decreased when it is combined with Rifabutin.
RifampicinThe serum concentration of Sunitinib can be decreased when it is combined with Rifampicin.
RifapentineThe serum concentration of Sunitinib can be decreased when it is combined with Rifapentine.
RifaximinThe serum concentration of Rifaximin can be increased when it is combined with Sunitinib.
RoflumilastRoflumilast may increase the immunosuppressive activities of Sunitinib.
SaquinavirThe serum concentration of Saquinavir can be increased when it is combined with Sunitinib.
SaxagliptinSaxagliptin may increase the hypoglycemic activities of Sunitinib.
SilodosinThe serum concentration of Silodosin can be increased when it is combined with Sunitinib.
SiltuximabThe serum concentration of Sunitinib can be decreased when it is combined with Siltuximab.
SimeprevirThe serum concentration of Sunitinib can be increased when it is combined with Simeprevir.
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Sunitinib.
SparfloxacinSparfloxacin may increase the hypoglycemic activities of Sunitinib.
St. John's WortThe serum concentration of Sunitinib can be decreased when it is combined with St. John's Wort.
StiripentolThe serum concentration of Sunitinib can be increased when it is combined with Stiripentol.
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Sunitinib.
TemsirolimusThe risk or severity of adverse effects can be increased when Temsirolimus is combined with Sunitinib.
TestosteroneTestosterone may increase the hypoglycemic activities of Sunitinib.
TocilizumabThe serum concentration of Sunitinib can be decreased when it is combined with Tocilizumab.
TofacitinibSunitinib may increase the immunosuppressive activities of Tofacitinib.
TolbutamideTolbutamide may increase the hypoglycemic activities of Sunitinib.
TopotecanThe serum concentration of Topotecan can be increased when it is combined with Sunitinib.
TranylcypromineTranylcypromine may increase the hypoglycemic activities of Sunitinib.
TrastuzumabTrastuzumab may increase the neutropenic activities of Sunitinib.
VerapamilThe serum concentration of Verapamil can be increased when it is combined with Sunitinib.
VildagliptinVildagliptin may increase the hypoglycemic activities of Sunitinib.
VincristineThe serum concentration of Vincristine can be increased when it is combined with Sunitinib.
VoriconazoleThe metabolism of Sunitinib can be decreased when combined with Voriconazole.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
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 development, cell proliferation, survival, differentiation, chemotaxis and migration. Plays an essential role in blood vessel development by promoting proliferation, migration and recruitment of peri...
Gene Name:
PDGFRB
Uniprot ID:
P09619
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
Human
Pharmacological action
yes
Actions
antagonist
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 survival, cell migration, macrophage function, chemotaxis, and cancer cell invasion. May play an essential role as a negative regulator of embryonic angiogenesis by inhibiting excessive proliferation ...
Gene Name:
FLT1
Uniprot ID:
P17948
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
Human
Pharmacological action
yes
Actions
antagonist
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 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...
Gene Name:
KIT
Uniprot ID:
P10721
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
Human
Pharmacological action
unknown
Actions
multitarget
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 embryonic hematopoiesis. Promotes proliferation, survival, migration and differentiation of endothelial cells. Promotes reorganization of the actin cytoskeleton. Isoforms lacking a transmembrane domai...
Gene Name:
KDR
Uniprot ID:
P35968
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
Human
Pharmacological action
unknown
Actions
antagonist
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 cardiovascular system during embryonic development. Promotes proliferation, survival and migration of endothelial cells, and regulates angiogenic sprouting. Signaling by activated FLT4 leads to enhanced pr...
Gene Name:
FLT4
Uniprot ID:
P35916
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
Human
Pharmacological action
unknown
Actions
multitarget
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. 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...
Gene Name:
FLT3
Uniprot ID:
P36888
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
Human
Pharmacological action
unknown
Actions
other/unknown
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 cells, especially mononuclear phagocytes, such as macrophages and monocytes. Promotes the release of proinflammatory chemokines in response to IL34 and CSF1, and thereby plays an important role in inn...
Gene Name:
CSF1R
Uniprot ID:
P07333
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
Human
Pharmacological action
unknown
Actions
antagonist
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 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...
Gene Name:
PDGFRA
Uniprot ID:
P16234
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
Human
Pharmacological action
unknown
Actions
substrate
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 reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
Kind
Protein
Organism
Human
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 unrelated compounds, including steroids, fatty acids, and xenobiotics.
Gene Name:
CYP3A5
Uniprot ID:
P20815
Molecular Weight:
57108.065 Da
References
  1. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
Kind
Protein
Organism
Human
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 unrelated compounds, including steroids, fatty acids, and xenobiotics.
Gene Name:
CYP3A7
Uniprot ID:
P24462
Molecular Weight:
57525.03 Da
References
  1. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]

Transporters

Kind
Protein
Organism
Human
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
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
Human
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
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 ]
Kind
Protein
Organism
Human
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
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
Human
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 from mitochondria to cytosol and from cytosol to extracellular space, and cellular export of hemin, and heme. Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from t...
Gene Name:
ABCG2
Uniprot ID:
Q9UNQ0
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 ]
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Drug created on May 16, 2007 14:11 / Updated on May 01, 2016 02:28