Lapatinib (GW-572016) Ditosylate

Lapatinib Ditosylate (GW572016, GW2016) is a potent EGFR and ErbB2 inhibitor with IC50 of 10.8 and 9.2 nM, respectively.

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Lapatinib (GW-572016) Ditosylate Chemical Structure

Lapatinib (GW-572016) Ditosylate Chemical Structure
Molecular Weight: 925.46

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Customer Reviews(7)

Quality Control & MSDS

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Product Information

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  • Research Area

Product Description

Biological Activity

Description Lapatinib Ditosylate (GW572016, GW2016) is a potent EGFR and ErbB2 inhibitor with IC50 of 10.8 and 9.2 nM, respectively.
Targets EGFR ErbB2
IC50 10.8 nM 9.2 nM [1]
In vitro Lapatinib Ditosylate weakly inhibits the activity of ErbB4 with IC50 of 367 nM, and displays >300-fold selectivity for EGFR and ErbB2 over other kinases such as c-Src, c-Raf, MEK, ERK, c-Fms, CDK1, CDK2, p38, Tie-2, and VEGFR2. Lapatinib Ditosylate significantly inhibits receptor autophosphorylation of EGFR and ErbB2 in a dose-dependent manner with IC50 of 170 nM and 80 nM, respectively in HN5 cells; as well as 210 nM and 60 nM, respectively in BT474 cells. Unlike OSI-774 and Iressa (ZD1839) which preferentially inhibit the growth of the EGFR-overexpressing cells, Lapatinib Ditosylate inhibits the growth of both EGFR- and ErbB2-overexpressing cells. Lapatinib Ditosylate displays higher inhibitory activity against EGFR- or ErbB2-overexpressing cells with IC50 of 0.09-0.21 μM, compared with cells expressing low levels of EGFR or ErbB2 with IC50 of 3-12 μM, and exhibits ~100-fold selectivity over the normal fibroblast cells. Lapatinib Ditosylate potently inhibits the outgrowth of EGFR-overexpressing HN5 and A-431 cells, as well as ErbB2-overexpressing BT474 and N87 cells, and significantly induces G1 arrest of HN5 cells and apoptosis of BT474 cells, which are associated with inhibition of AKT phosphorylation. [1]
In vivo Oral administration of Lapatinib Ditosylate (~100 mg/kg) twice daily significantly inhibits the growth of BT474 and HN5 xenografts in a dose-dependent manner. [1]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

In vitro kinase assays The IC50 values for inhibition of enzyme activity are generated by measuring inhibition of phosphorylation of a peptide substrate. The intracellular kinase domains of EGFR and ErbB2 are purified from a baculovirus expression system. EGFR and ErbB2 reactions are performed in 96-well polystyrene round-bottomed plates in a final volume of 45 μL. Reaction mixtures contain 50 mM 4-morpholinepropanesulfonic acid (pH 7.5), 2 mM MnCl2, 10 μM ATP, 1 μCi of [γ33P] ATP/reaction, 50 μM Peptide A [Biotin-(amino hexonoic acid)-EEEEYFELVAKKK-CONH2], 1 mM dithiothreitol, and 1 μL of DMSO containing serial dilutions of Lapatinib beginning at 10 μM. The reaction is initiated by adding the indicated purified type-1 receptor intracellular domain. The amount of enzyme added is 1 pmol/reaction (20 nM). Reactions are terminated after 10 minutes at 23°C by adding 45 μL of 0.5% phosphoric acid in water. The terminated reaction mix (75 μL) is transferred to phosphocellulose filter plates. The plates are filtered and washed three times with 200 μL of 0.5% phosphoric acid. Scintillation cocktail (50 μL) is added to each well, and the assay is quantified by counting in a Packard Topcount. IC50 values are generated from 10-point dose-response curves.

Cell Assay: [1]

Cell lines HFF, MCF-7, T47D, A-431, HN5, BT474, N87, CaLu-3, HB4a, and HB4a c5.2
Concentrations Dissolved in DMSO, final concentrations ~100 μM
Incubation Time 72 hours
Method Cells are exposed to various concentrations of Lapatinib for 72 hours. Relative cell number is estimated using methylene blue staining. The absorbance at 620 nm is read in a Spectra microplate reader. Cell death and cell cycle analysis are assessed by propidium iodide staining and antibody detection of incorporated BrdUrd and staining with propidium iodide.

Animal Study: [1]

Animal Models CD-1 nude female mice implanted s.c. with HN5 cells, and C.B-17 SCID female mice implanted s.c. with BT474 cells
Dosages ~100 mg/kg
Administration Orally twice daily
Solubility 15% Captisol, 5 mg/mL
1

References

Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT01705340 Terminated Adenocarcinoma of the Gastroesophageal Junction|HER2-positive Breast Cancer|Male Breast Cancer|Recurrent Breast Cancer|Recurrent Esophageal Cancer|Recurrent Gastric Cancer|Stage IIIC Breast Cancer|Sta National Cancer Institute (NCI) 2012-09 Phase 1
NCT01783756 Recruiting Central Nervous System Metastases|HER2-positive Breast Cancer|Male Breast Cancer|Recurrent Breast Cancer|Stage IV Breast Cancer Jonsson Comprehensive Cancer Center 2013-06 Phase 1|Phase 2
NCT01868503 Recruiting Male Breast Cancer|Recurrent Breast Cancer|Stage IIIA Breast Cancer|Stage IIIB Breast Cancer|Stage IIIC Breast Cancer Stanford University|National Cancer Institute (NCI) 2013-07 Phase 2
NCT01873833 Recruiting HER2-positive Breast Cancer|Recurrent Breast Cancer|Stage IV Breast Cancer USC/Norris Comprehensive Cancer Center|National Cancer Institute (NCI) 2013-07 Phase 2
NCT01947023 Recruiting Recurrent Thyroid Cancer National Cancer Institute (NCI) 2013-08 Phase 1

Chemical Information

Download Lapatinib (GW-572016) Ditosylate SDF
Molecular Weight (MW) 925.46
Formula

C29H26ClFN4O4S.2C7H8O3S

CAS No. 388082-77-7
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Syonnyms GW-572016
Solubility (25°C) * In vitro DMSO 185 mg/mL (199 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 15% Captisol, 5 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-(5-((2-(methylsulfonyl)ethylamino)methyl)furan-2-yl)quinazolin-4-amine,di4-methylbenzenesulfonate

Preparing Stock Solutions

Stock Solution (1ml DMSO) 1mM 10mM 20mM 30mM
Mass(mg) 0.92546 9.2546 18.5092 27.7638

Research Area

Customer Reviews (7)


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Rating
Source Int J Proteomics 2011 2011, Article ID 215496. Lapatinib (GW-572016) Ditosylate purchased from Selleck
Method CEER assay
Cell Lines H1734 cell line
Concentrations 0-10 μM
Incubation Time 4 h
Results HER1 and/or HER2 pathway-activated cell lines, H1734 , had their activation blocked by the HER1/2 kinase inhibitors Lapatinib.

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Rating
Source Biochem Pharmacol 2011 82(10), 1457-1466. . Lapatinib (GW-572016) Ditosylate purchased from Selleck
Method Evaluation of differentiation
Cell Lines MOLM-13 cells, HL-60 cells
Concentrations 5 μM
Incubation Time
Results In a first series of experiments, we assessed four signs of morphological differentiation, May-Gruenwald-Giemsa staining of MOLM-13 cells demonstrated that dasatinib induced a dose-dependent decrease in cytoplasmic basophilia and in the nucleo-cytoplasmic ratio. Dasatinib also led to the appearance of dented nuclei and cytoplasmic granulation( Fig.A and B).In HL-60 cells,dasatinib(5 μM) once more exhibited the highest differentiation-inducing capacity. Thus dasatinib diminished basophilia of the cytoplasm concomitantly with the nucleo-cytoplasmic ratio, and induced the appearance of nuclear lobulation and cytoplasmic granules(Fig. G). Next, we determined the degree of CD11b expression, a marker indicating myeloid differentiation, in TKI-treated MOLM-13 dasatinib exhibited the most pronounced capacity to increase CD11b surface expression( Fig. C and D).To corroborate the TKI-driven differentiation, we quantified the enzymatic activity of alkaline phosphatase by means of the NBT-reduction assay after an incubation period of 6 days in MOLM-13 cells.,Once again, the NBT-reductive activity was highest in cells treated with dasatinib, which was as active as the positive control, ATRA( Fig. E and F)

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Rating
Source Carcinogenesis 2010 31, 1948–1955 . Lapatinib (GW-572016) Ditosylate purchased from Selleck
Method Luciferase assay
Cell Lines LNCaP-AI cells, LNCaP cells
Concentrations 20 μM
Incubation Time 24 h
Results EGF significantly stimulates the promoter activity of sPLA2-IIa gene in both LNCaP and LNCaP-AI cells (shown in LNCaP-AI cells), whereas Lapatinib and other inhibitors tested downregulated the promoter activity both at the basal level (shown in LNCaP cells) and in response to EGF stimulation (shown in LNCaP-AI cells).

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Rating
Source Dr. Zhang of Tianjin Medical University. Lapatinib (GW-572016) Ditosylate purchased from Selleck
Method Western blot
Cell Lines T47D cells
Concentrations 0-5 nM
Incubation Time 3 h
Results

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Rating
Source Biochem Pharmacol 2011 82(10), 1457-1466. Lapatinib (GW-572016) Ditosylate purchased from Selleck
Method MTT assay
Cell Lines MOLM-13 cells, HL-60 cells
Concentrations 1-15 μM
Incubation Time 24/48/72 h
Results Lapatinib and other TKI decreased the viability of the two myeloid cell lines in a dose- and time-dependent manner. Nevertheless, the anti-leukemic efficacy of the four TKI varied considerably in both cell lines.

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Rating
Source Mol Cancer Ther 2011 10, 697-707. Lapatinib (GW-572016) Ditosylate purchased from Selleck
Method Cell viability assay
Cell Lines murine rhabdo myosarcom primary cell
Concentrations 5 μmol/L
Incubation Time 72 h
Results "The results of the cell viability assay showed that NVP-AEW541 alone led to an unexpected increase in cell growth at moderate doses for the NVP-AEW541 resistant cell culture. However , the cell growth inhibition could be cooperatively improved by addition of lapatinib (cooperativity index 0.1) , although lapatinib alone had no substantial effect on naive or resistant tumor cells (Fig. A and B). To examine the activity of Igf1r a nd Her2 in NVP-AEW 541 resistant primary tumor cell lines, Resistant cell cultures treated with lapatinib showed decreased p-Her2 levels; however, no difference in Her2 activity was observed in cells treated with NVP-AEW541. When the resistant cells were treated with lapatinib, a surprising increase in the levels of p-Igf1r was observed in comparison vehicle treated cells (Fig. C)

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Rating
Source Carcinogenesis 2010 31, 1948–1955. Lapatinib (GW-572016) Ditosylate purchased from Selleck
Method ELISA
Cell Lines LNCaP-AI cells
Concentrations 20 μM
Incubation Time 24 h
Results Lapatinib, LY294002 and Bortezomib significantly inhibited sPLA2-IIa secretion, whereas Erlotinib, Gefitinib and CI-1033 had a moderate effect in LNCaP-AI cells.

Product Citations (13)

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