Lapatinib

EGFR/HER2 inhibitor,potent,selective and reversible CAS# 231277-92-2

Lapatinib

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Quality Control of Lapatinib

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Chemical structure

Lapatinib

3D structure

Chemical Properties of Lapatinib

Cas No. 231277-92-2 SDF Download SDF
PubChem ID 208908 Appearance Powder
Formula C29H26ClFN4O4S M.Wt 581.06
Type of Compound N/A Storage Desiccate at -20°C
Synonyms GW572016
Solubility DMSO : ≥ 39 mg/mL (67.12 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[(2-methylsulfonylethylamino)methyl]furan-2-yl]quinazolin-4-amine
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
Standard InChIKey BCFGMOOMADDAQU-UHFFFAOYSA-N
Standard 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)
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

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

Protocol

Kinase Assay [1]
The intracellular kinase domains of EGFR, ErbB-2, and ErbB4 are purified from a baculovirus expression system. EGFR, ErbB-2, and ErbB-4 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 [γ-33P] 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 min 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[1].

Cell Assay [1]
Cells are plated in 96-well plates, in the media, at the following densities: HFF and HN5, 1000 cells/well and BT474, 5000 cells/well. After 24 h, the cells are exposed to vehicle (0.3% DMSO) or Lapatinib (1 nM, 10 nM, 100 nM, 1μM, 10μM, and 100μM). Lapatinib is removed from the cells after 72 h and is replaced by either DMEM containing 10% FBS and 50 μg/mL Gentamicin (HFF and HN5) or RPMI containing 10% FBS and 50 μg/mL Gentamicin (BT474). Methylene blue staining is performed at the time points over a total period of 16 days[1].

Animal Administration [1][3]
Mice[1] CD-1 nude female mice are used for HN5 human tumor xenografts, which are initiated by injection of a cell suspension in PBS:Matrigel (1:1). C.B-17 SCID female mice are used for BT474 human tumor xenografts, which are initiated by implantation of tumor fragments (20-100 mg) from established tumors. Tumor cells and fragments are implanted by s.c. injection in the right flank. The s.c. tumors are measured with calipers, and mice are weighed twice weekly. Tumor weight is estimated from tumor volume using this formula: length×width2/2=tumor volume (mm3). Treatment begins when tumors are palpable, 3-5 mm in diameter. Lapatinib (30 and 100 mg/kg) is administered p.o. twice daily for 21 days in a vehicle of sulfo-butyl-ether-β-cyclodextrin 10% aqueous solution (CD10). Rats[3] Wistar rats (12-week-old albino males) are randomly assigned to three groups: control (C, n=8), Trastuzumab (T, n=8) and Lapatinib (L, n=8) treatments. The control animals are untreated, but the others in groups T and Lapatinib are administered with the chemotherapy drugs. Trastuzumab is delivered once at a dose of 10 mg/kg/day via intraperitoneal injection on the first day of the study. Lapatinib is administered daily at a dose of 100 mg/kg/day by oral gavage for 7 consecutive days. The selected doses are equivalent to those used in the clinics. On day 8, anesthesia is induced by a single intraperitoneal injection of ketamine and xylazine (50 and 5 mg/kg, respectively). The blood samples are collected and the hearts are removed for biochemical analysis.

References:
[1]. Rusnak DW, 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 Dec;1(2):85-94. [2]. O'Neill F, et al. Gene expression changes as markers of early lapatinib response in a panel of breast cancer cell lines. Mol Cancer. 2012 Jun 18;11(1):41. [3]. Eryilmaz U, et al. S100A1 as a Potential Diagnostic Biomarker for Assessing Cardiotoxicity and Implications for the Chemotherapy of Certain Cancers. PLoS One. 2015 Dec 18;10(12):e0145418. [4]. Ni J, et al. Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases. Nat Med. 2016 Jul;22(7):723-6. [5]. Oncogene. 2016 Jun 9;35(23):2961-70. doi: 10.1038/onc.2015.377. Epub 2015 Dec 7.

Lapatinib Dilution Calculator

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Lapatinib Molarity Calculator

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Preparing Stock Solutions of Lapatinib

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.721 mL 8.605 mL 17.2099 mL 34.4199 mL 43.0248 mL
5 mM 0.3442 mL 1.721 mL 3.442 mL 6.884 mL 8.605 mL
10 mM 0.1721 mL 0.8605 mL 1.721 mL 3.442 mL 4.3025 mL
50 mM 0.0344 mL 0.1721 mL 0.3442 mL 0.6884 mL 0.8605 mL
100 mM 0.0172 mL 0.086 mL 0.1721 mL 0.3442 mL 0.4302 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.

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Background on Lapatinib

Lapatinib (also known as GW572016), a member of the 4-anilinoquinazoline class of kinase inhibitors, is a potent, reversible and selective small-molecule inhibitor of both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER-2) tyrosine kinases that inhibits recombinant EGFR and HER-2 tyrosine kinases in cell-free biochemical kinase assays with values of 50% inhibition concentration IC50 of 10.8 nmol/L and 9.3 nmol/L respectively. Lapatinib interferes with the adenosine triphosphate binding in the tyrosine kinases domains of both EGFR and HER-2 resulting in the inhibition of auto-phosphorylation and resultant downstream signaling activities (such as cellular proliferation and survival).

Reference

Alison Reid, Laura Vidal, Heather Shaw and Johann de Bono. Dual inhibition of ErbB1 (EGFR/HER1) and ErbB2 (HER2/neu). European Journal of Cancer 43 (2007) 481-489

Norio Kondo, Mamoru Tsukuda, Yukari Ishiguro, Machiko Kimura, Kyoko Fujita, Atsuko Sakakibara, Hideaki Takahashi, Gabor Toth and Hideki Matsuda. Antitumor effects of lapatinib (GW572016), a dual inhibitor of EGFR and HER-2, in combination with cisplatin or paclitaxel on head and neck squamous cell carcinoma. Oncology Reports 23: 957-963, 2010

Zev A. Wainberg, Adrian Anghel, Amrita J. Desai, Raul Ayala, Tong Luo, Brent Safran, Marlena S. Fejzo, J. Randolph Hecht, Denni J. Slamon and Richard S. Finn. Lapatinib, a dual EGFR and HER2 kinase inhibitor, selectively inhibits HER2-amplified human gastric cancer cells and is synergistic with trastuzumab in vitro and in vivo. Clin Cancer Res 2010; 16(5): 1509-1519

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References on Lapatinib

Phase Ib dose-finding trial of lapatinib plus pegylated liposomal doxorubicin in advanced HER2-positive breast cancer.[Pubmed:28341957]

Cancer Chemother Pharmacol. 2017 May;79(5):863-871.

PURPOSE: Combination of anthracyclines with trastuzumab is hampered by cardiotoxicity. Pegylated liposomal doxorubicin and Lapatinib could represent a safer alternative to combination therapy. METHODS: In this phase Ib study with 3 + 3 dose escalation design, patients with HER2-positive advanced breast cancer received pegylated liposomal doxorubicin 30 mg/m(2) intravenously on day 1 plus Lapatinib 1250 (level 1) or 1500 (level 2) mg/day orally on days 1-21 of each 21-day cycle. The aims were to establish the maximum tolerated dose at first cycle, and the activity and safety of multiple cycles. RESULTS: Nine patients out of 11 enrolled were evaluable: 3 at level 1 and 6 at level 2. No dose-limiting toxicities occurred at dose level 1, while 1 (grade 3 diarrhea) occurred at dose level 2, leading to the expansion of this cohort to 6 patients, with no further dose-limiting toxicities. Main grade 1-2 toxicities at first cycle were leucopenia, diarrhea, elevated transaminases, mucositis. Three patients had grade 3 toxicities at subsequent cycles, including colitis, anorexia, stomatitis plus hand-foot syndrome. One partial response, 5 disease stabilizations, and 3 disease progressions were reported. CONCLUSIONS: Combination of pegylated liposomal doxorubicin and Lapatinib is feasible and potentially active in pretreated HER2-positive advanced breast cancer patients. TRIAL REGISTRATION: NCT02131506 (ClinicalTrials.gov identifier).

FOXO1 Suppression is a Determinant of Acquired Lapatinib-Resistance in HER2-Positive Gastric Cancer Cells Through MET Upregulation.[Pubmed:28343375]

Cancer Res Treat. 2018 Jan;50(1):239-254.

PURPOSE: Lapatinib is a candidate drug for treatment of trastuzumab-resistant, human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). Unfortunately, Lapatinib resistance renders this drug ineffective. The present study investigated the implication of forkhead box O1 (FOXO1) signaling in the acquired Lapatinib resistance in HER2-positive GC cells. MATERIALS AND METHODS: Lapatinib-resistant GC cell lines (SNU-216 LR2-8) were generated in vitro by chronic exposure of Lapatinib-sensitive, HER2-positive SNU-216 cells to Lapatinib. SNU-216 LR cells with FOXO1 overexpression were generated by stable transfection of a constitutively active FOXO1 mutant (FOXO1A3). HER2 and MET in SNU-216 LR cells were downregulated using RNA interference. The sensitivity of GC cells to Lapatinib and/or cisplatin was determined by crystal violet assay. In addition, Western blot analysis, luciferase reporter assay and reverse transcription-polymerase chain reaction were performed. RESULTS: SNU-216 LR cells showed upregulations of HER2 and MET, but downregulation of FOXO1 compared to parental SNU-216 cells. FOXO1 overexpression in SNU-216 LR cells significantly suppressed resistance to Lapatinib and/or cisplatin. In addition, FOXO1 negatively controlled HER2 and MET at the transcriptional level and was negatively controlled by these molecules at the post-transcriptional level. A positive crosstalk was shown between HER2 and MET, each of which increased resistance to Lapatinib and/or cisplatin. CONCLUSION: FOXO1 serves as an important linker between HER2 and MET signaling pathways through negative crosstalks and is a key regulator of the acquired Lapatinib resistance in HER2-positive GC cells. These findings provide a rationale for establishing a novel treatment strategy to overcome Lapatinib resistance in a subtype of GC patients.

HR+HER2- breast cancers with growth factor receptor-mediated EMT have a poor prognosis and lapatinib downregulates EMT in MCF-7 cells.[Pubmed:28349782]

Tumour Biol. 2017 Mar;39(3):1010428317695028.

Despite an overall good prognosis, a significant proportion of patients with hormone receptor positive human epidermal growth factor receptor 2 negative breast cancers develop distant metastases. The metastatic potential of epithelial cells is known to be regulated by tumor-stromal interaction and mediated by epithelial-to-mesenchymal transition. Hormone receptor positive human epidermal growth factor receptor 2 negative tumors were used to estimate markers of epithelial-to-mesenchymal transition, and the luminal breast cancer cell line MCF-7 was used to examine the interactions between integrins and growth factor receptors in causation of epithelial-to-mesenchymal transition. A total of 140 primary tumors were sub-divided into groups enriched for the markers of epithelial-to-mesenchymal transition (snail family transcriptional repressor 2 and integrin beta6) versus those with low levels. Within the epithelial-to-mesenchymal transition+ tumors, there was a positive correlation between the transcripts of integrin beta6 and growth factor receptors-human epidermal growth factor receptor 2 and epidermal growth factor receptor. In tumors enriched for epithelial-to-mesenchymal transition markers, patients with tumors with the highest quartile of growth factor receptor transcripts had a shorter disease-free survival compared to patients with low growth factor receptor expression by Kaplan-Meier analysis (log rank, p = 0.03). Epithelial-to-mesenchymal transition was induced in MCF-7 cells by treatment with transforming growth factor beta 1 and confirmed by upregulation of SNAI1 and SNAI2 transcripts, increase of vimentin and integrin beta6 protein, and repression of E-cadherin. Treatment of these cells with the dual-specificity tyrosine-kinase inhibitor Lapatinib led to downregulation of epithelial-to-mesenchymal transition as indicated by lower levels of SNAI1 and SNAI2 transcripts, integrin alphavbeta6, and matrix metalloproteinase 9 protein. The results suggest that synergistic interactions between growth factor receptors and integrin beta6 could mediate epithelial-to-mesenchymal transition and migration in a subset of luminal breast cancers and Lapatinib might be effective in disrupting this interaction.

Description

Lapatinib (GW572016) 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.

Keywords:

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