Lapatinib (GW-572016) Ditosylate

Catalog No.S1028
5 5 22 Product Citations

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 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 ErbB2 [1] EGFR [1] ErbB4 [1] c-Src [1] C-Raf-1 [1]

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IC50 9.2 nM 10.8 nM 367 nM 3.5 μM >10 μM
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
Formulation Formulated in a vehicle of sulfo-butyl-ether-β-cyclodextrin 10% aqueous solution (CD10)
Dosages ~100 mg/kg
Administration Orally twice daily
Solubility 15% Captisol, 5 mg/mL
* 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.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Rusnak DW, et al. Mol Cancer Ther, 2001, 1(2), 85-94.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2014-10-24)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02238509 Not yet recruiting Metastatic Breast Cancer Consorzio Oncotech November 2014 Phase 2
NCT02230553 Not yet recruiting Colorectal Cancer The Netherlands Cancer Institute|GlaxoSmithKline September 2014 Phase 1|Phase 2
NCT02213042 Not yet recruiting Neoplasms, Breast GlaxoSmithKline August 2014 Phase 2
NCT02158507 Recruiting Metastatic Triple Negative Breast Cancer University of Alabama at Birmingham|Scariot Foundation|Gl  ...more University of Alabama at Birmingham|Scariot Foundation|GlaxoSmithKline|AbbVie July 2014 --
NCT02101905 Suspended Adult Anaplastic Astrocytoma|Adult Anaplastic Ependymoma|Adult Anaplastic Oligodendroglioma|Adult Giant Cell Glioblastoma|Adult Glioblastoma|Adult  ...more Adult Anaplastic Astrocytoma|Adult Anaplastic Ependymoma|Adult Anaplastic Oligodendroglioma|Adult Giant Cell Glioblastoma|Adult Glioblastoma|Adult Gliosarcoma|Adult Mixed Glioma|Recurrent Adult Brain Tumor National Cancer Institute (NCI) March 2014 --

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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
Synonyms
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

Research Area

Customer Reviews (7)


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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.

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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 Biochem Pharmacol 2011 82, 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 Biochem Pharmacol 2011 82, 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 Int J Proteomics 2011 2011, 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 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

Product Citations (22)

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