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Identification
NameLapatinib
Accession NumberDB01259  (DB02584)
TypeSmall Molecule
GroupsApproved, Investigational
Description

Lapatinib is an anti-cancer drug developed by GlaxoSmithKline (GSK) as a treatment for solid tumours such as breast and lung cancer. It was approved by the FDA on March 13, 2007, for use in patients with advanced metastatic breast cancer in conjunction with the chemotherapy drug Capecitabine. Lapatinib is human epidermal growth factor receptor type 2 (HER2/ERBB2) and epidermal growth factor receptor (HER1/EGFR/ERBB1) tyrosine kinases inhibitor. It binds to the intracellular phosphorylation domain to prevent receptor autophosphorylation upon ligand binding.

Structure
Thumb
Synonyms
FMM
GW 572016
Lapatinib tosilate hydrate
N-(3-chloro-4-((3-Fluorophenyl)methoxy)phenyl)-6-(5-(((2-(methylsulfonyl)ethyl)amino)methyl)-2-furanyl)-4-quinazolinamine
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine
Tykerb
External Identifiers
  • GW 572016
  • GW572016
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Tykerbtablet250 mg/1oralGlaxo Smith Kline Llc2007-03-162016-04-23Us
Tykerbtablet250 mgoralNovartis Pharmaceuticals Canada Inc2009-06-05Not applicableCanada
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International Brands
NameCompany
TycerbNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Lapatinib ditosylate
388082-78-8
Thumb
  • InChI Key: XNRVGTHNYCNCFF-UHFFFAOYSA-N
  • Monoisotopic Mass: 942.1841276
  • Average Mass: 943.47
DBSALT001785
Categories
UNII0VUA21238F
CAS number231277-92-2
WeightAverage: 581.058
Monoisotopic: 580.134731942
Chemical FormulaC29H26ClFN4O4S
InChI KeyInChIKey=BCFGMOOMADDAQU-UHFFFAOYSA-N
InChI
InChI=1S/C29H26ClFN4O4S/c1-40(36,37)12-11-32-16-23-7-10-27(39-23)20-5-8-26-24(14-20)29(34-18-33-26)35-22-6-9-28(25(30)15-22)38-17-19-3-2-4-21(31)13-19/h2-10,13-15,18,32H,11-12,16-17H2,1H3,(H,33,34,35)
IUPAC Name
N-{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}-6-(5-{[(2-methanesulfonylethyl)amino]methyl}furan-2-yl)quinazolin-4-amine
SMILES
CS(=O)(=O)CCNCC1=CC=C(O1)C1=CC2=C(C=C1)N=CN=C2NC1=CC(Cl)=C(OCC2=CC(F)=CC=C2)C=C1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as quinazolinamines. These are heterocyclic aromatic compounds containing a quianazoline moiety substituted by one or more amine groups.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassNaphthyridines
Sub ClassQuinazolines
Direct ParentQuinazolinamines
Alternative Parents
Substituents
  • Quinazolinamine
  • Phenol ether
  • Aralkylamine
  • Halobenzene
  • Fluorobenzene
  • Chlorobenzene
  • Aminopyrimidine
  • Alkyl aryl ether
  • Imidolactam
  • Benzenoid
  • Pyrimidine
  • Monocyclic benzene moiety
  • Aryl halide
  • Aryl fluoride
  • Aryl chloride
  • Heteroaromatic compound
  • Sulfonyl
  • Sulfone
  • Furan
  • Oxacycle
  • Azacycle
  • Secondary amine
  • Ether
  • Secondary aliphatic amine
  • Hydrocarbon derivative
  • Organosulfur compound
  • Organooxygen compound
  • Organonitrogen compound
  • Organofluoride
  • Organochloride
  • Organohalogen compound
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationIndicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress the human epidermal receptor type 2 (HER2) protein and who have received prior therapy including an anthracycline, a taxane, and trastuzuma.
PharmacodynamicsLapatinib is a small molecule and a member of the 4-anilinoquinazoline class of kinase inhibitors. An anti-cancer drug, lapatinib was developed by GlaxoSmithKline (GSK) as a treatment for solid tumours such as breast and lung cancer. It was approved by the FDA on March 13, 2007, for use in patients with advanced metastatic breast cancer in conjunction with the chemotherapy drug capecitabine.
Mechanism of actionLapatinib is a 4-anilinoquinazoline kinase inhibitor of the intracellular tyrosine kinase domains of both epidermal growth factor receptor (HER1/EGFR/ERBB1) and human epidermal growth factor receptor type 2 (HER2/ERBB2)with a dissociation half-life of ≥300 minutes. Lapatinib inhibits ERBB-driven tumor cell growth in vitro and in various animal models. An additive effect was demonstrated in an in vitro study when lapatinib and 5-florouracil (the active metabolite of capecitabine) were used in combination in the 4 tumor cell lines tested. The growth inhibitory effects of lapatinib were evaluated in trastuzumab-conditioned cell lines. Lapatinib retained significant activity against breast cancer cell lines selected for long-term growth in trastuzumab-containing medium in vitro. These in vitro findings suggest non-cross-resistance between these two agents.
Related Articles
AbsorptionAbsorption following oral administration of lapatinib is incomplete and variable.
Volume of distributionNot Available
Protein bindingHighly bound (>99%) to albumin and alpha-1 acid glycoprotein
Metabolism

Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8 to a variety of oxidated metabolites, none of which accounts for more than 14% of the dose recovered in the feces or 10% of lapatinib concentration in plasma.

Route of eliminationLapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8 to a variety of oxidated metabolites, none of which accounts for more than 14% of the dose recovered in the feces or 10% of lapatinib concentration in plasma.
Half lifeSingle-dose terminal half life: 14.2 hours Effective multiple-dose half life: 24 hours
ClearanceNot Available
ToxicityThere has been a report of one patient who took 3,000 mg of lapatinib for 10 days. This patient had grade 3 diarrhea and vomiting on day 10.
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+1.0
Blood Brain Barrier+0.6201
Caco-2 permeable-0.5858
P-glycoprotein substrateSubstrate0.7403
P-glycoprotein inhibitor IInhibitor0.5414
P-glycoprotein inhibitor IINon-inhibitor0.7799
Renal organic cation transporterNon-inhibitor0.7442
CYP450 2C9 substrateNon-substrate0.6688
CYP450 2D6 substrateNon-substrate0.7644
CYP450 3A4 substrateSubstrate0.6619
CYP450 1A2 substrateInhibitor0.5386
CYP450 2C9 inhibitorNon-inhibitor0.5544
CYP450 2D6 inhibitorNon-inhibitor0.7861
CYP450 2C19 inhibitorInhibitor0.5274
CYP450 3A4 inhibitorInhibitor0.8065
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.9104
Ames testNon AMES toxic0.543
CarcinogenicityNon-carcinogens0.6788
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.5867 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Strong inhibitor0.537
hERG inhibition (predictor II)Inhibitor0.8417
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Tabletoral250 mg/1
Tabletoral250 mg
Prices
Unit descriptionCostUnit
Tykerb 250 mg tablet28.4USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2317589 No2007-08-082019-01-08Canada
CA2413134 No2010-05-112021-06-28Canada
US6391874 No1997-07-112017-07-11Us
US6713485 No2000-09-292020-09-29Us
US6727256 No1999-01-082019-01-08Us
US6828320 No1997-07-112017-07-11Us
US7157466 No2001-11-192021-11-19Us
US8513262 No1999-01-082019-01-08Us
US8821927 No2009-09-182029-09-18Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
logP5.4Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0223 mg/mLALOGPS
logP5.18ALOGPS
logP4.64ChemAxon
logS-4.4ALOGPS
pKa (Strongest Acidic)15.99ChemAxon
pKa (Strongest Basic)7.2ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area106.35 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity152.42 m3·mol-1ChemAxon
Polarizability61.19 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

DrugSyn.org

US6727256
General References
  1. Nelson MH, Dolder CR: Lapatinib: a novel dual tyrosine kinase inhibitor with activity in solid tumors. Ann Pharmacother. 2006 Feb;40(2):261-9. Epub 2006 Jan 17. [PubMed:16418322 ]
  2. Burris HA 3rd: Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib. Oncologist. 2004;9 Suppl 3:10-5. [PubMed:15163842 ]
  3. Burris HA 3rd, Hurwitz HI, Dees EC, Dowlati A, Blackwell KL, O'Neil B, Marcom PK, Ellis MJ, Overmoyer B, Jones SF, Harris JL, Smith DA, Koch KM, Stead A, Mangum S, Spector NL: Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J Clin Oncol. 2005 Aug 10;23(23):5305-13. Epub 2005 Jun 13. [PubMed:15955900 ]
  4. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006 Dec 28;355(26):2733-43. [PubMed:17192538 ]
  5. Johnston SR, Leary A: Lapatinib: a novel EGFR/HER2 tyrosine kinase inhibitor for cancer. Drugs Today (Barc). 2006 Jul;42(7):441-53. [PubMed:16894399 ]
  6. Tevaarwerk AJ, Kolesar JM: Lapatinib: a small-molecule inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor-2 tyrosine kinases used in the treatment of breast cancer. Clin Ther. 2009;31 Pt 2:2332-48. doi: 10.1016/j.clinthera.2009.11.029. [PubMed:20110044 ]
  7. Medina PJ, Goodin S: Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clin Ther. 2008 Aug;30(8):1426-47. doi: 10.1016/j.clinthera.2008.08.008. [PubMed:18803986 ]
External Links
ATC CodesL01XE07
AHFS CodesNot Available
PDB Entries
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Lapatinib.
AmodiaquineThe serum concentration of Amodiaquine can be increased when it is combined with Lapatinib.
AprepitantThe serum concentration of Lapatinib can be increased when it is combined with Aprepitant.
AripiprazoleThe serum concentration of Aripiprazole can be increased when it is combined with Lapatinib.
AtazanavirThe serum concentration of Lapatinib can be increased when it is combined with Atazanavir.
BexaroteneThe serum concentration of Lapatinib can be decreased when it is combined with Bexarotene.
BoceprevirThe serum concentration of Lapatinib can be increased when it is combined with Boceprevir.
BosentanThe serum concentration of Lapatinib can be decreased when it is combined with Bosentan.
BosutinibThe serum concentration of Bosutinib can be increased when it is combined with Lapatinib.
Brentuximab vedotinThe serum concentration of Brentuximab vedotin can be increased when it is combined with Lapatinib.
CarbamazepineThe serum concentration of Lapatinib can be decreased when it is combined with Carbamazepine.
CeritinibThe serum concentration of Lapatinib can be increased when it is combined with Ceritinib.
CitalopramLapatinib may increase the QTc-prolonging activities of Citalopram.
ClarithromycinThe serum concentration of Lapatinib can be increased when it is combined with Clarithromycin.
CobicistatThe serum concentration of Lapatinib can be increased when it is combined with Cobicistat.
ColchicineThe serum concentration of Colchicine can be increased when it is combined with Lapatinib.
ConivaptanThe serum concentration of Lapatinib 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 Lapatinib.
DabrafenibThe serum concentration of Lapatinib can be decreased when it is combined with Dabrafenib.
DarunavirThe serum concentration of Lapatinib can be increased when it is combined with Darunavir.
DasatinibThe serum concentration of Lapatinib can be increased when it is combined with Dasatinib.
DeferasiroxThe serum concentration of Lapatinib can be decreased when it is combined with Deferasirox.
DexamethasoneThe serum concentration of Lapatinib can be decreased when it is combined with Dexamethasone.
DofetilideLapatinib may increase the QTc-prolonging activities of Dofetilide.
DoxorubicinThe serum concentration of Doxorubicin can be increased when it is combined with Lapatinib.
EdoxabanThe serum concentration of Edoxaban can be increased when it is combined with Lapatinib.
EnzalutamideThe serum concentration of Lapatinib can be decreased when it is combined with Enzalutamide.
EverolimusThe serum concentration of Everolimus can be increased when it is combined with Lapatinib.
FlibanserinThe serum concentration of Flibanserin can be increased when it is combined with Lapatinib.
FluconazoleThe metabolism of Lapatinib can be decreased when combined with Fluconazole.
FosaprepitantThe serum concentration of Lapatinib can be increased when it is combined with Fosaprepitant.
FosphenytoinThe serum concentration of Lapatinib can be decreased when it is combined with Fosphenytoin.
Fusidic AcidThe serum concentration of Lapatinib can be increased when it is combined with Fusidic Acid.
GoserelinLapatinib may increase the QTc-prolonging activities of Goserelin.
HydrocodoneThe serum concentration of Hydrocodone can be increased when it is combined with Lapatinib.
IdelalisibThe serum concentration of Lapatinib can be increased when it is combined with Idelalisib.
IndinavirThe serum concentration of Lapatinib can be increased when it is combined with Indinavir.
ItraconazoleThe serum concentration of Lapatinib can be increased when it is combined with Itraconazole.
IvacaftorThe serum concentration of Lapatinib can be increased when it is combined with Ivacaftor.
KetoconazoleThe serum concentration of Lapatinib can be increased when it is combined with Ketoconazole.
LedipasvirThe serum concentration of Ledipasvir can be increased when it is combined with Lapatinib.
LeuprolideLapatinib may increase the QTc-prolonging activities of Leuprolide.
LomitapideThe serum concentration of Lomitapide can be increased when it is combined with Lapatinib.
LuliconazoleThe serum concentration of Lapatinib can be increased when it is combined with Luliconazole.
MifepristoneThe serum concentration of Lapatinib can be increased when it is combined with Mifepristone.
MitotaneThe serum concentration of Lapatinib can be decreased when it is combined with Mitotane.
NaloxegolThe serum concentration of Naloxegol can be increased when it is combined with Lapatinib.
NefazodoneThe serum concentration of Lapatinib can be increased when it is combined with Nefazodone.
NelfinavirThe serum concentration of Lapatinib can be increased when it is combined with Nelfinavir.
NetupitantThe serum concentration of Lapatinib can be increased when it is combined with Netupitant.
NimodipineThe serum concentration of Nimodipine can be increased when it is combined with Lapatinib.
PalbociclibThe serum concentration of Lapatinib can be increased when it is combined with Palbociclib.
PazopanibLapatinib may increase the QTc-prolonging activities of Pazopanib.
PhenobarbitalThe serum concentration of Lapatinib can be decreased when it is combined with Phenobarbital.
PhenytoinThe serum concentration of Lapatinib can be decreased when it is combined with Phenytoin.
PimozideThe serum concentration of Pimozide can be increased when it is combined with Lapatinib.
PosaconazoleThe serum concentration of Lapatinib can be increased when it is combined with Posaconazole.
PrimidoneThe serum concentration of Lapatinib can be decreased when it is combined with Primidone.
PrucaloprideThe serum concentration of Prucalopride can be increased when it is combined with Lapatinib.
RanolazineThe serum concentration of Ranolazine can be increased when it is combined with Lapatinib.
RifabutinThe serum concentration of Lapatinib can be decreased when it is combined with Rifabutin.
RifampicinThe serum concentration of Lapatinib can be decreased when it is combined with Rifampicin.
RifapentineThe serum concentration of Lapatinib can be decreased when it is combined with Rifapentine.
RifaximinThe serum concentration of Rifaximin can be increased when it is combined with Lapatinib.
RitonavirThe serum concentration of Lapatinib can be increased when it is combined with Ritonavir.
SaquinavirThe serum concentration of Lapatinib can be increased when it is combined with Saquinavir.
SilodosinThe serum concentration of Silodosin can be increased when it is combined with Lapatinib.
SiltuximabThe serum concentration of Lapatinib can be decreased when it is combined with Siltuximab.
SimeprevirThe serum concentration of Lapatinib can be increased when it is combined with Simeprevir.
St. John's WortThe serum concentration of Lapatinib can be decreased when it is combined with St. John's Wort.
StiripentolThe serum concentration of Lapatinib can be increased when it is combined with Stiripentol.
TelaprevirThe serum concentration of Lapatinib can be increased when it is combined with Telaprevir.
TelithromycinThe serum concentration of Lapatinib can be increased when it is combined with Telithromycin.
TesmilifeneThe serum concentration of Lapatinib can be decreased when it is combined with Tesmilifene.
TocilizumabThe serum concentration of Lapatinib can be decreased when it is combined with Tocilizumab.
TopotecanThe serum concentration of Topotecan can be increased when it is combined with Lapatinib.
TorasemideThe metabolism of Torasemide can be decreased when combined with Lapatinib.
VerapamilThe serum concentration of Lapatinib can be increased when it is combined with Verapamil.
VincristineThe serum concentration of Vincristine can be increased when it is combined with Lapatinib.
VoriconazoleThe serum concentration of Lapatinib can be increased when it is combined with Voriconazole.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
General Function:
Ubiquitin protein ligase binding
Specific Function:
Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TGFA/TGF-alpha, amphiregulin, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF. Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on ke...
Gene Name:
EGFR
Uniprot ID:
P00533
Molecular Weight:
134276.185 Da
References
  1. Xia W, Mullin RJ, Keith BR, Liu LH, Ma H, Rusnak DW, Owens G, Alligood KJ, Spector NL: Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene. 2002 Sep 12;21(41):6255-63. [PubMed:12214266 ]
  2. Grana TM, Sartor CI, Cox AD: Epidermal growth factor receptor autocrine signaling in RIE-1 cells transformed by the Ras oncogene enhances radiation resistance. Cancer Res. 2003 Nov 15;63(22):7807-14. [PubMed:14633707 ]
  3. Xia W, Liu LH, Ho P, Spector NL: Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016. Oncogene. 2004 Jan 22;23(3):646-53. [PubMed:14737100 ]
  4. Zhou H, Kim YS, Peletier A, McCall W, Earp HS, Sartor CI: Effects of the EGFR/HER2 kinase inhibitor GW572016 on EGFR- and HER2-overexpressing breast cancer cell line proliferation, radiosensitization, and resistance. Int J Radiat Oncol Biol Phys. 2004 Feb 1;58(2):344-52. [PubMed:14751502 ]
  5. Langer CJ: Emerging role of epidermal growth factor receptor inhibition in therapy for advanced malignancy: focus on NSCLC. Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):991-1002. [PubMed:14967461 ]
  6. Burris HA 3rd: Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib. Oncologist. 2004;9 Suppl 3:10-5. [PubMed:15163842 ]
  7. Wood ER, Truesdale AT, McDonald OB, Yuan D, Hassell A, Dickerson SH, Ellis B, Pennisi C, Horne E, Lackey K, Alligood KJ, Rusnak DW, Gilmer TM, Shewchuk L: A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res. 2004 Sep 15;64(18):6652-9. [PubMed:15374980 ]
  8. Vazquez-Martin A, Oliveras-Ferraros C, Cufi S, Del Barco S, Martin-Castillo B, Menendez JA: Lapatinib, a dual HER1/HER2 tyrosine kinase inhibitor, augments basal cleavage of HER2 extracellular domain (ECD) to inhibit HER2-driven cancer cell growth. J Cell Physiol. 2011 Jan;226(1):52-7. doi: 10.1002/jcp.22333. [PubMed:20658522 ]
  9. Johnston SR, Leary A: Lapatinib: a novel EGFR/HER2 tyrosine kinase inhibitor for cancer. Drugs Today (Barc). 2006 Jul;42(7):441-53. [PubMed:16894399 ]
  10. Tevaarwerk AJ, Kolesar JM: Lapatinib: a small-molecule inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor-2 tyrosine kinases used in the treatment of breast cancer. Clin Ther. 2009;31 Pt 2:2332-48. doi: 10.1016/j.clinthera.2009.11.029. [PubMed:20110044 ]
  11. Medina PJ, Goodin S: Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clin Ther. 2008 Aug;30(8):1426-47. doi: 10.1016/j.clinthera.2008.08.008. [PubMed:18803986 ]
  12. 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
yes
Actions
antagonist
General Function:
Transmembrane signaling receptor activity
Specific Function:
Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding. Essential component of a neuregulin-receptor complex, although neuregulins do not interact with it alone. GP30 is a potential ligand for this receptor. Regulates outgrowth and stabilization of peripheral microtubules (MTs). Upon ERBB2 activation, the MEMO1-...
Gene Name:
ERBB2
Uniprot ID:
P04626
Molecular Weight:
137909.27 Da
References
  1. Xia W, Liu LH, Ho P, Spector NL: Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016. Oncogene. 2004 Jan 22;23(3):646-53. [PubMed:14737100 ]
  2. Zhou H, Kim YS, Peletier A, McCall W, Earp HS, Sartor CI: Effects of the EGFR/HER2 kinase inhibitor GW572016 on EGFR- and HER2-overexpressing breast cancer cell line proliferation, radiosensitization, and resistance. Int J Radiat Oncol Biol Phys. 2004 Feb 1;58(2):344-52. [PubMed:14751502 ]
  3. Langer CJ: Emerging role of epidermal growth factor receptor inhibition in therapy for advanced malignancy: focus on NSCLC. Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):991-1002. [PubMed:14967461 ]
  4. Burris HA 3rd: Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib. Oncologist. 2004;9 Suppl 3:10-5. [PubMed:15163842 ]
  5. Wood ER, Truesdale AT, McDonald OB, Yuan D, Hassell A, Dickerson SH, Ellis B, Pennisi C, Horne E, Lackey K, Alligood KJ, Rusnak DW, Gilmer TM, Shewchuk L: A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res. 2004 Sep 15;64(18):6652-9. [PubMed:15374980 ]
  6. Grana TM, Sartor CI, Cox AD: Epidermal growth factor receptor autocrine signaling in RIE-1 cells transformed by the Ras oncogene enhances radiation resistance. Cancer Res. 2003 Nov 15;63(22):7807-14. [PubMed:14633707 ]
  7. Xia W, Mullin RJ, Keith BR, Liu LH, Ma H, Rusnak DW, Owens G, Alligood KJ, Spector NL: Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene. 2002 Sep 12;21(41):6255-63. [PubMed:12214266 ]
  8. Vazquez-Martin A, Oliveras-Ferraros C, Cufi S, Del Barco S, Martin-Castillo B, Menendez JA: Lapatinib, a dual HER1/HER2 tyrosine kinase inhibitor, augments basal cleavage of HER2 extracellular domain (ECD) to inhibit HER2-driven cancer cell growth. J Cell Physiol. 2011 Jan;226(1):52-7. doi: 10.1002/jcp.22333. [PubMed:20658522 ]
  9. Johnston SR, Leary A: Lapatinib: a novel EGFR/HER2 tyrosine kinase inhibitor for cancer. Drugs Today (Barc). 2006 Jul;42(7):441-53. [PubMed:16894399 ]
  10. Tevaarwerk AJ, Kolesar JM: Lapatinib: a small-molecule inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor-2 tyrosine kinases used in the treatment of breast cancer. Clin Ther. 2009;31 Pt 2:2332-48. doi: 10.1016/j.clinthera.2009.11.029. [PubMed:20110044 ]
  11. Medina PJ, Goodin S: Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clin Ther. 2008 Aug;30(8):1426-47. doi: 10.1016/j.clinthera.2008.08.008. [PubMed:18803986 ]
  12. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
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. Medina PJ, Goodin S: Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clin Ther. 2008 Aug;30(8):1426-47. doi: 10.1016/j.clinthera.2008.08.008. [PubMed:18803986 ]
  2. van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. doi: 10.1016/j.ctrv.2009.08.004. Epub 2009 Sep 5. [PubMed:19733976 ]
  3. Teng WC, Oh JW, New LS, Wahlin MD, Nelson SD, Ho HK, Chan EC: Mechanism-based inactivation of cytochrome P450 3A4 by lapatinib. Mol Pharmacol. 2010 Oct;78(4):693-703. doi: 10.1124/mol.110.065839. Epub 2010 Jul 12. [PubMed:20624855 ]
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. Medina PJ, Goodin S: Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clin Ther. 2008 Aug;30(8):1426-47. doi: 10.1016/j.clinthera.2008.08.008. [PubMed:18803986 ]
  2. van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. doi: 10.1016/j.ctrv.2009.08.004. Epub 2009 Sep 5. [PubMed:19733976 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Steroid 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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme...
Gene Name:
CYP2C8
Uniprot ID:
P10632
Molecular Weight:
55824.275 Da
References
  1. Medina PJ, Goodin S: Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clin Ther. 2008 Aug;30(8):1426-47. doi: 10.1016/j.clinthera.2008.08.008. [PubMed:18803986 ]
  2. van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. doi: 10.1016/j.ctrv.2009.08.004. Epub 2009 Sep 5. [PubMed:19733976 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Steroid hydroxylase activity
Specific Function:
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine.
Gene Name:
CYP2C19
Uniprot ID:
P33261
Molecular Weight:
55930.545 Da
References
  1. Medina PJ, Goodin S: Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clin Ther. 2008 Aug;30(8):1426-47. doi: 10.1016/j.clinthera.2008.08.008. [PubMed:18803986 ]
  2. van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. doi: 10.1016/j.ctrv.2009.08.004. Epub 2009 Sep 5. [PubMed:19733976 ]

Transporters

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. Dai CL, Tiwari AK, Wu CP, Su XD, Wang SR, Liu DG, Ashby CR Jr, Huang Y, Robey RW, Liang YJ, Chen LM, Shi CJ, Ambudkar SV, Chen ZS, Fu LW: Lapatinib (Tykerb, GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP-binding cassette subfamily B member 1 and G member 2. Cancer Res. 2008 Oct 1;68(19):7905-14. doi: 10.1158/0008-5472.CAN-08-0499. [PubMed:18829547 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Tap2 binding
Specific Function:
Involved in the transport of antigens from the cytoplasm to the endoplasmic reticulum for association with MHC class I molecules. Also acts as a molecular scaffold for the final stage of MHC class I folding, namely the binding of peptide. Nascent MHC class I molecules associate with TAP via tapasin. Inhibited by the covalent attachment of herpes simplex virus ICP47 protein, which blocks the pep...
Gene Name:
TAP1
Uniprot ID:
Q03518
Molecular Weight:
87216.855 Da
References
  1. Dai CL, Tiwari AK, Wu CP, Su XD, Wang SR, Liu DG, Ashby CR Jr, Huang Y, Robey RW, Liang YJ, Chen LM, Shi CJ, Ambudkar SV, Chen ZS, Fu LW: Lapatinib (Tykerb, GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP-binding cassette subfamily B member 1 and G member 2. Cancer Res. 2008 Oct 1;68(19):7905-14. doi: 10.1158/0008-5472.CAN-08-0499. [PubMed:18829547 ]
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Drug created on May 16, 2007 11:27 / Updated on April 30, 2016 02:27