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Lapatinib Ditosylate

EGFR/HER2 inhibitor,potent and selective CAS# 388082-78-8

Lapatinib Ditosylate

Catalog No. BCC2083----Order now to get a substantial discount!

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Chemical structure

Lapatinib Ditosylate

3D structure

Chemical Properties of Lapatinib Ditosylate

Cas No. 388082-78-8 SDF Download SDF
PubChem ID 208909 Appearance Powder
Formula C29H26ClFN4O4S 2C7H8O3S M.Wt 785.3
Type of Compound N/A Storage Desiccate at -20°C
Solubility Soluble in DMSO
Chemical Name benzenesulfonic acid;N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[(2-methylsulfonylethylamino)methyl]furan-2-yl]quinazolin-4-amine;hydrate
SMILES CS(=O)(=O)CCNCC1=CC=C(O1)C2=CC3=C(C=C2)N=CN=C3NC4=CC(=C(C=C4)OCC5=CC(=CC=C5)F)Cl.C1=CC=C(C=C1)S(=O)(=O)O.C1=CC=C(C=C1)S(=O)(=O)O.O
Standard InChIKey CJCNEWWARIPAEG-UHFFFAOYSA-N
Standard InChI InChI=1S/C29H26ClFN4O4S.2C6H6O3S.H2O/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;2*7-10(8,9)6-4-2-1-3-5-6;/h2-10,13-15,18,32H,11-12,16-17H2,1H3,(H,33,34,35);2*1-5H,(H,7,8,9);1H2
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Lapatinib Ditosylate

DescriptionLapatinib Ditosylate (GW572016, GW2016) is a potent inhibitor of EGFR and ErbB2 with IC50 of 10.8 and 9.2 nM, respectively.
TargetsEGFRErbB2    
IC5010.8 nM9.2 nM    

Lapatinib Ditosylate Dilution Calculator

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Lapatinib Ditosylate Molarity Calculator

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Preparing Stock Solutions of Lapatinib Ditosylate

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.2734 mL 6.367 mL 12.734 mL 25.468 mL 31.835 mL
5 mM 0.2547 mL 1.2734 mL 2.5468 mL 5.0936 mL 6.367 mL
10 mM 0.1273 mL 0.6367 mL 1.2734 mL 2.5468 mL 3.1835 mL
50 mM 0.0255 mL 0.1273 mL 0.2547 mL 0.5094 mL 0.6367 mL
100 mM 0.0127 mL 0.0637 mL 0.1273 mL 0.2547 mL 0.3183 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

Research Update of Lapatinib Ditosylate

1. Lapatinib ditosylate: expanding therapeutic options for receptor tyrosine-protein kinase erbB-2-positive breast cancer. Drugs Today (Barc). 2011 May;47(5):335-45. doi: 10.1358/dot.2011.47.5.1584110.
Abstract
Lapatinib ditosylate is a tyrosine kinase inhibitor targeting HER2 receptor that exhibits activity in transtuzumab-resistant advanced tumors, recurrent local advanced inflammatory breast cancer and brain metastases. The combination of lapatinib ditosylate , trastuzumab and paclitaxel significantly improved pathological complete response in Neo-ALTTO trails.
2. RON confers lapatinib resistance in HER2-positive breast cancer cells. Cancer Lett. 2013 Oct 28;340(1):43-50. doi: 10.1016/j.canlet.2013.06.022. Epub 2013 Jun 27.
Abstract
RON plays an important role in lapatinib-resistance mediation, where small-molecular RON inhibitors and siRNA could restore lapatinib sensitivity in SK-BR-3-LR cells.
4. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1183-92. doi: 10.1016/S1470-2045(13)70411-X. Epub 2013 Oct 4.
Abstract
Lapatinib plus paclitaxel and lapatinib plus trastuzumab were evaluated respectively for their effects on tumor response in HER2+ breast cancer patients with prior treatment of doxorubicin plus cyclophosphamide.
5. Addition of amino acid moieties to lapatinib increases the anti-cancer effect via amino acid transporters. Biopharm Drug Dispos. 2014 Jan;35(1):60-9. doi: 10.1002/bdd.1872. Epub 2013 Nov 19.
Abstract
The enhanced anticancer activity of val-lapatinib and tyr-lapatinib in various cancer cells, including human breast cancer cells and lung cancer cells, is possible caused by increased uptake of them into cancer cells via amino acid transporter, since they were found to inhibited glutamine transport in cancer cells.

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Background on Lapatinib Ditosylate

Lapatinib Ditosylateis a selective dual inhibitor of ErbB-2 and EGFR with IC50 value against ErbB-2 and EGFR of 9.8 and 10.2 nM in vitro, respectively. [1]
The EGFR and ErbB-2 all are the type I receptor tyrosine kinase that exists on the cell surface and have been recognised as potential targets for cancers. A conformational change happens by binding of its specific ligands in the receptor then activates the kinase domain. Whereas, erbB2 is generally thought that it has no known direct activating ligand, and it may become active by heterodimerization with other ligand-bound family members. EGFR dimerization stimulates protein-tyrosine kinase activity and elicits downstream signaling by several other proteins. These proteins initiate several signal transduction pathway. EGFR and ErbB-2 are well known to stimulate cell division through the Ras pathway, and resulting in cell growth through the PI3K pathway. [1]
Lapatinib is a selective inhibitor of the ErbB-2 and EGFR. Lapatinib was>300 fold selective for ErbB-2 and EGFR over other kinases, such as MEK, ERK. Lapatinib likely competed intracellular ATP with Erb-2 and EGFR,then inhibit the activation of them. Lapatinib inhibited the growth of human tumor cells in a cell-based proliferation assay. The IC50 values was < 0.16nM in the ErbB-2- and EGFR -overexpressing cell lines: HN5, A-431. In the cell lines expressing low level ErbB-2- and EGFR. The IC50 values were about 25-fold higher than in the overexpressing cell lines. Lapatinib resulted in G1 arrest at 10nM in HN5 cells. Lapatinib inhibited phos phorylated Er k1/2 100% at 5 nM in an erbB2 overexpressing cell line. Lapatinib inhibited EGF stimulated p-Erk1/ 2 at 1 nM and complet ely inh ibited p-AKT.[1, 2]
In human breast cancer xenografts, tumor volumes in mice at the dose of 75 mg/kg of lapatinib twice daily were significantly smaller than the vehicle control, at day 21.[3] Lapatinib completely inhibited the growth of HN5 and BT474 human tumor xenografts at the 100 mg/kg dose, twice daily.[1]
References:
1.Rusnak DW, Lackey K, Affleck K, Wood ER, Alligood KJ, Rhodes N, Keith BR, Murray DM, Knight WB, Mullin RJ et al: The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol Cancer Ther 2001, 1(2):85-94.
2.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, 21(41):6255-6263.
3.Konecny GE, Pegram MD, Venkatesan N, Finn R, Yang G, Rahmeh M, Untch M, Rusnak DW, Spehar G, Mullin RJ et al: Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res 2006, 66(3):1630-1639.

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References on Lapatinib Ditosylate

Lapatinib ditosylate: expanding therapeutic options for receptor tyrosine-protein kinase erbB-2-positive breast cancer.[Pubmed:22013564]

Drugs Today (Barc). 2011 May;47(5):335-45.

Receptor tyrosine-protein kinase erbB-2 (HER2)-positive breast cancer is a specific entity with an aggressive behavior. Trastuzumab, a monoclonal antibody targeting erbB-2 (HER2) deeply transformed the outcome in patients. Nevertheless, resistance to trastuzumab is still a major concern. Lapatinib Ditosylate is an orally available, small molecule targeting the tyrosine activity of the HER2 receptor. Lapatinib as a single agent and in combination therapy showed interesting activity in trastuzumab-resistant advanced tumors. In addition, lapatinib use seemed suitable in recurrent locally advanced inflammatory breast cancer and brain metastases. More recently, the Neo-ALTTO (NeoAdjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) trial showed that lapatinib in combination with trastuzumab and paclitaxel significantly improved the pathological complete response in a neoadjuvant setting. Several clinical trials are still ongoing and data that may change current clinical practice are awaited with much interest.

Lapatinib ditosylate GlaxoSmithKline.[Pubmed:12964069]

IDrugs. 2003 Sep;6(9):886-93.

Lapatinib Ditosylate, an ErbB-2 and EGFR dual tyrosine kinase inhibitor, is being developed by GlaxoSmithKline plc for the potential treatment of solid tumors.

A review of lapatinib ditosylate in the treatment of refractory or advanced breast cancer.[Pubmed:18472989]

Ther Clin Risk Manag. 2007 Aug;3(4):665-73.

Breast cancer remains a leading cause of disease and death among women throughout the world. Despite advances in drug therapy, development of novel and improved drugs for breast cancer continues to be of great interest. Lapatinib is a novel dual receptor tyrosine kinase inhibitor that is a selective and potent inhibitor of ErbB-1 and ErbB-2 tyrosine kinases, both of which are growth promoting factors overexpressed in some breast cancers. Cell-based assays have proven lapatinib to be a potent inhibitor of ErbB-1 and ErbB-2 activation and breast cancer cell proliferation. In pharmacokinetic studies, lapatinib has shown mostly linear elimination kinetics over the daily dose range of 10-1600 mg and is metabolized by CYP3A4/5 and CYP2C19. Phase I, II, and III clinical trials involving lapatinib as monotherapy or in combination have shown promise for the treatment of advanced and metastatic breast cancer. Drug-drug interactions may occur secondary to concomitant administration of either CYP450 inhibitors or inducers. While lapatinib appear to be a promising addition to breast cancer therapy, several questions remain to be answered before its optimal role is elucidated.

Description

Lapatinib ditosylate monohydrate (GW572016 ditosylate monohydrate) is a potent inhibitor of the ErbB-2 and EGFR tyrosine kinase domains with IC50 values against purified EGFR and ErbB-2 of 10.2 and 9.8 nM, respectively.

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