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Research ArticleCellular and Molecular

Target Binding Properties and Cellular Activity of Afatinib (BIBW 2992), an Irreversible ErbB Family Blocker

Flavio Solca, Goeran Dahl, Andreas Zoephel, Gerd Bader, Michael Sanderson, Christian Klein, Oliver Kraemer, Frank Himmelsbach, Eric Haaksma and Guenther R. Adolf
Journal of Pharmacology and Experimental Therapeutics November 2012, 343 (2) 342-350; DOI: https://doi.org/10.1124/jpet.112.197756
Flavio Solca
Boehringer Ingelheim RCV GmbH & Co. KG., Vienna, Austria (F.S., G.D., A.Z., G.B., M.S., C.K., O.K., E.H., G.R.A.); and Boehringer Ingelheim Pharma GmbH & Co. KG., Biberach/Riss, Germany (F.H.)
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Goeran Dahl
Boehringer Ingelheim RCV GmbH & Co. KG., Vienna, Austria (F.S., G.D., A.Z., G.B., M.S., C.K., O.K., E.H., G.R.A.); and Boehringer Ingelheim Pharma GmbH & Co. KG., Biberach/Riss, Germany (F.H.)
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Andreas Zoephel
Boehringer Ingelheim RCV GmbH & Co. KG., Vienna, Austria (F.S., G.D., A.Z., G.B., M.S., C.K., O.K., E.H., G.R.A.); and Boehringer Ingelheim Pharma GmbH & Co. KG., Biberach/Riss, Germany (F.H.)
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Gerd Bader
Boehringer Ingelheim RCV GmbH & Co. KG., Vienna, Austria (F.S., G.D., A.Z., G.B., M.S., C.K., O.K., E.H., G.R.A.); and Boehringer Ingelheim Pharma GmbH & Co. KG., Biberach/Riss, Germany (F.H.)
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Michael Sanderson
Boehringer Ingelheim RCV GmbH & Co. KG., Vienna, Austria (F.S., G.D., A.Z., G.B., M.S., C.K., O.K., E.H., G.R.A.); and Boehringer Ingelheim Pharma GmbH & Co. KG., Biberach/Riss, Germany (F.H.)
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Christian Klein
Boehringer Ingelheim RCV GmbH & Co. KG., Vienna, Austria (F.S., G.D., A.Z., G.B., M.S., C.K., O.K., E.H., G.R.A.); and Boehringer Ingelheim Pharma GmbH & Co. KG., Biberach/Riss, Germany (F.H.)
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Oliver Kraemer
Boehringer Ingelheim RCV GmbH & Co. KG., Vienna, Austria (F.S., G.D., A.Z., G.B., M.S., C.K., O.K., E.H., G.R.A.); and Boehringer Ingelheim Pharma GmbH & Co. KG., Biberach/Riss, Germany (F.H.)
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Frank Himmelsbach
Boehringer Ingelheim RCV GmbH & Co. KG., Vienna, Austria (F.S., G.D., A.Z., G.B., M.S., C.K., O.K., E.H., G.R.A.); and Boehringer Ingelheim Pharma GmbH & Co. KG., Biberach/Riss, Germany (F.H.)
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Eric Haaksma
Boehringer Ingelheim RCV GmbH & Co. KG., Vienna, Austria (F.S., G.D., A.Z., G.B., M.S., C.K., O.K., E.H., G.R.A.); and Boehringer Ingelheim Pharma GmbH & Co. KG., Biberach/Riss, Germany (F.H.)
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Guenther R. Adolf
Boehringer Ingelheim RCV GmbH & Co. KG., Vienna, Austria (F.S., G.D., A.Z., G.B., M.S., C.K., O.K., E.H., G.R.A.); and Boehringer Ingelheim Pharma GmbH & Co. KG., Biberach/Riss, Germany (F.H.)
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Abstract

Deregulation of the ErbB (proto-oncogene B of the avian erythroblastosis virus AEV-H strain) receptor network is well recognized as an oncogenic driver in epithelial cancers. Several targeted drugs have been developed, including antibodies and small-molecule kinase inhibitors, each of them characterized by distinct patterns of ErbB receptor interactions. Understanding the precise pharmacological properties of these compounds is important for optimal use in clinical practice. Afatinib [BIBW 2992; N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-2-butenamide] is an ATP-competitive anilinoquinazoline derivative harboring a reactive acrylamide group. It was designed to covalently bind and irreversibly block enzymatically active ErbB receptor family members. Here, we show by X-ray crystallography the covalent binding of afatinib to wild-type epidermal growth factor receptor (EGFR) and by mass spectrometry the covalent interaction with EGFR, EGFRL858R/T790M, human epidermal growth factor receptor 2 (HER2), and ErbB-4. Afatinib potently inhibits the enymatic activity of ErbB-4 (EC50 = 1 nM) and the proliferation of cancer cell lines driven by multiple ErbB receptor aberrations at concentrations below 100 nM. N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-2-butanamide (BI 37781), a close analog of afatinib lacking the acrylamide group and thus incapable of covalent bond formation, had similar potency on cells driven by EGFR or EGFRL858R, but less or no detectable activity on cells expressing EGFRL858R/ T790M HER2 or ErbB-4. These results stress the importance of the acrylamide group and show that afatinib differs from approved ErbB targeting agents by irreversibly inhibiting the kinase activity of all ErbB family members. They provide a mechanistic rationale for the distinct pharmacological features of this compound and explain the clinical activity seen in some patients who are resistant to antibody or kinase inhibitor therapy because of secondary mutations or ErbB receptor “reprogramming.”

Footnotes

  • The work was supported entirely by Boehringer-Ingelheim.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.197756.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    EGF
    epidermal growth factor
    EGFR
    EGF receptor
    HER
    human EGFR
    WT
    wild type
    GST
    glutathione transferase
    KD
    kinase domain
    PBS
    phosphate-buffered saline
    SPR
    surface plasmon resonance
    DTT
    dithiothreitol
    MS
    mass spectrometry
    MS/MS
    tandem MS
    BIBW 2992
    N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-2-butenamide
    BI 37781
    N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-2-butanamide.

  • Received June 25, 2012.
  • Accepted August 9, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 343 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 343, Issue 2
1 Nov 2012
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Research ArticleCellular and Molecular

Afatinib, an Irreversible Inhibitor of EGFR, HER2, and ErbB4

Flavio Solca, Goeran Dahl, Andreas Zoephel, Gerd Bader, Michael Sanderson, Christian Klein, Oliver Kraemer, Frank Himmelsbach, Eric Haaksma and Guenther R. Adolf
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 342-350; DOI: https://doi.org/10.1124/jpet.112.197756

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Research ArticleCellular and Molecular

Afatinib, an Irreversible Inhibitor of EGFR, HER2, and ErbB4

Flavio Solca, Goeran Dahl, Andreas Zoephel, Gerd Bader, Michael Sanderson, Christian Klein, Oliver Kraemer, Frank Himmelsbach, Eric Haaksma and Guenther R. Adolf
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 342-350; DOI: https://doi.org/10.1124/jpet.112.197756
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