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    Afatinib (BIBW2992)
    Afatinib (BIBW2992)

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0536
    CAS #: 850140-72-6Purity ≥98%

    Description: Afatinib (formerly BIBW 2992; BIBW-2992; brand name: Gilotrif), is a potent, covalent/irreversible, and orally bioavailable dual (EGFR/ErbB) receptor tyrosine kinase (RTK) inhibitor with anticancer activity. Afatinib is an FDA approved anticancer drug used to treat non-small cell lung carcinoma (NSCLC). It is sold under the brand name of Gilotrif in the USA. It irreversibly binds to and inhibits EGFR/HER2 including EGFR(wt), EGFR(L858R), EGFR(L858R/T790M) and HER2 with IC50 of 0.5 nM, 0.4 nM, 10 nM and 14 nM in cell-free assays, respectively; and is 100-fold more active against Gefitinib-resistant L858R-T790M EGFR mutant.

    References: Oncogene. 2008 Aug 7;27(34):4702-11; Br J Cancer. 2008 Jan 15;98(1):80-5.

    Related CAS: 850140-72-6 or 850140-72-6 (free base); 850140-73-7 (dimaleate); 439081-18-2 (free base)

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    Molecular Weight (MW)485.94
    FormulaC24H25ClFN5O3
    CAS No.439081-18-2 (free base); or 850140-72-6 (free base) 
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 97 mg/mL (199.6 mM)
    Water: <1 mg/mL
    Ethanol: 15 mg/mL (30.9 mM)
    Solubility (In vivo)2% DMSO+30% PEG 300+5% Tween 80+ddH2O: 10 mg/mL
    SynonymsBIBW2992. Afatinib free base; BIBW 2992; BIBW 2992; Afatinib; trade name: Gilotrif, Tomtovok and Tovok. 

    Chemical Name: (S,E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide.

    SMILES Code: O=C(NC1=CC2=C(NC3=CC=C(F)C(Cl)=C3)N=CN=C2C=C1O[[email protected]@H]4COCC4)/C=C/CN(C)C


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    In Vitro

    In vitro activity: BIBW2992 shows potent activity against both wild-type and mutant forms of EGFR and HER2. It is similar to Gefitinib in potency against L858R EGFR, but about 100-fold more active against the Gefitinib resistant L858R-T790M EGFR double mutant. BIBW2992 exhibits potent effects on both EGFR and HER2 phosphorylation in vivo. It compares favorably to reference compounds (such as Lapatinib et al.) in all cell types tested, such as human epidermoid carcinoma cell line A431 expressing wt EGFR, murine NIH-3T3 cells transfected with wt HER2, as well as breast cancer cell line BT-474 and gastric cancer cell line NCI-N87, which express endogenous HER2.


    Kinase Assay: The wild type tyrosine kinase domain of the human EGFR as well as that of the EGFR L858R/T790M double mutant are fused to Glutathione-S-transferase (GST), and extracted. Enzyme activity is then assayed in the presence of the inhibitor BIBW2992, serially diluted in 50% DMSO. A random polymer pEY (4:1) is used as substrate and biotinylated pEY (bio-pEY) is added as a tracer substrate. The kinase domain of HER2 is cloned using the baculovirus system and extracted similarly to that of EGFR kinase. Details of assays for EGFR, HER2, SRC, BIRK and VEGFR2 kinase activity are available in Supplementary information.


    Cell Assay: 1 × 104 NSCLC cells are transferred into each well of a 96-well plate and cultured overnight in serum-free media for the EGFR phosphorylation assay. After addition of BIBW2992 on the next day, the plates are incubated at 37 °C for 1 hour. EGF-stimulation is done using 100 ng/mL for 10 min at room temperature. Cells are washed with ice cold PBS, extracted with 120 μL HEPEX buffer per well and shaken at room temperature for 1 hour. In all 2 × 104cells per well is used for the HER2 phosphorylation assay. Streptavidin precoated plates are coated with anti-EGFR-biotin at 1:100 dilution in blocking buffer and c-erb2/HER2 oncoprotein Ab-5(Clone N24)-Biotin. Cell extracts is then transferred to the antibody-coated wells and incubated at room temperature for 1 hour. Extinction is measured at 450 nm.

    In VivoDaily oral administration of BIBW2992 at 20 mg/kg for 25 days results in dramatic tumor regression with a cumulative treated/control tumor volume ratio (T/C ratio) of 2%. Reduced phosphorylation of EGFR and AKT is confirmed by immunohistochemical staining of tissue sections. Therefore, like lapatinib and neratinib, BIBW2992 is a next generation tyrosine kinase inhibitor (TKI) that inhibits human epidermal growth factor receptor 2 (Her2) and epidermal growth factor receptor (EGFR) kinases irreversibly. BIBW2992 is not only active against EGFR mutations targeted by first generation TKIs like Erlotinib or Gefitinib, but also against those insensitive to these standard therapies.
    Animal modelAthymic NMRI-nu/nu female mice
    Formulation & DosageDissolved in 0.5% methocellulose-0.4% polysorbate-80 (Tween 80); 20 mg/kg; Oral gavage
    References

    Oncogene. 2008 Aug 7;27(34):4702-11; Br J Cancer. 2008 Jan 15;98(1):80-5.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    Afatinib (BIBW2992)

    Afatinib (BIBW2992)

    Afatinib (BIBW2992)

    Afatinib covalently binds to cysteine number 797 of the epidermal growth factor receptor (EGFR) via a Michael addition (IC50 = 0.5 nM). Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel Frühjahr 2013. (in German)


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