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PDBsum entry 4g5p
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Transferase/transferase inhibitor
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PDB id
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4g5p
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References listed in PDB file
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Key reference
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Title
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Target binding properties and cellular activity of afatinib (bibw 2992), An irreversible erbb family blocker.
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Authors
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F.Solca,
G.Dahl,
A.Zoephel,
G.Bader,
M.Sanderson,
C.Klein,
O.Kraemer,
F.Himmelsbach,
E.Haaksma,
G.R.Adolf.
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Ref.
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J Pharmacol Exp Ther, 2012,
343,
342-350.
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PubMed id
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Abstract
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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, EGFR(L858R/T790M), human epidermal growth factor receptor 2 (HER2), and
ErbB-4. Afatinib potently inhibits the enymatic activity of ErbB-4 (EC(50) = 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 EGFR(L858R), but less or no detectable activity on cells expressing
EGFR(L858R/ 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."
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