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PDBsum entry 3ika
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References listed in PDB file
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Key reference
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Title
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Novel mutant-Selective egfr kinase inhibitors against egfr t790m.
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Authors
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W.Zhou,
D.Ercan,
L.Chen,
C.H.Yun,
D.Li,
M.Capelletti,
A.B.Cortot,
L.Chirieac,
R.E.Iacob,
R.Padera,
J.R.Engen,
K.K.Wong,
M.J.Eck,
N.S.Gray,
P.A.Jänne.
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Ref.
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Nature, 2009,
462,
1070-1074.
[DOI no: ]
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PubMed id
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Abstract
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The clinical efficacy of epidermal growth factor receptor (EGFR) kinase
inhibitors in EGFR-mutant non-small-cell lung cancer (NSCLC) is limited by the
development of drug-resistance mutations, including the gatekeeper T790M
mutation. Strategies targeting EGFR T790M with irreversible inhibitors have had
limited success and are associated with toxicity due to concurrent inhibition of
wild-type EGFR. All current EGFR inhibitors possess a structurally related
quinazoline-based core scaffold and were identified as ATP-competitive
inhibitors of wild-type EGFR. Here we identify a covalent pyrimidine EGFR
inhibitor by screening an irreversible kinase inhibitor library specifically
against EGFR T790M. These agents are 30- to 100-fold more potent against EGFR
T790M, and up to 100-fold less potent against wild-type EGFR, than
quinazoline-based EGFR inhibitors in vitro. They are also effective in murine
models of lung cancer driven by EGFR T790M. Co-crystallization studies reveal a
structural basis for the increased potency and mutant selectivity of these
agents. These mutant-selective irreversible EGFR kinase inhibitors may be
clinically more effective and better tolerated than quinazoline-based
inhibitors. Our findings demonstrate that functional pharmacological screens
against clinically important mutant kinases represent a powerful strategy to
identify new classes of mutant-selective kinase inhibitors.
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Figure 3.
Figure 3: Crystal structure of WZ4002 bound to EGFR T790M. a,
Chemical structures of WZ8040 and WZ4002 are shown schematically
in a manner resembling the conformation adopted in complex with
the kinase. b, Crystal structure of WZ4002 in complex with EGFR
T790M mutant (PDB ID 3IKA). WZ4002 binds the active conformation
of the kinase, with both the regulatory C-helix and the
‘DFG’ segment of the activation loop in their inward, active
positions. The EGFR kinase is shown in a ribbon representation
(blue) with the bound inhibitor in yellow. Side-chain and
main-chain atoms are shown for selected residues that contact
the compound. Expected hydrogen bonds to the backbone amide and
carbonyl atoms of Met 793 are indicated by dashed lines. Note
also the covalent bond with Cys 797. The structure was refined
to a crystallographic R value of 21.3% (R[free] = 25.4%) with
data extending to 2.9-Å resolution (see Methods for
further crystallographic details).
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Figure 4.
Figure 4: WZ4002 inhibits EGFR phosphorylation and induces
significant tumour regression in murine models of EGFR T790M.
a, Two doses separated by 16 h of WZ4002 (2.5 mg kg^-1 or 25 mg
kg^-1) or vehicle were administered to EGFR delE746_A750/T790M
or L858R/T790M mice with MRI-confirmed tumours. The mice were
killed, the lungs isolated, grossly dissected and subjected to
cell lysis. Cell extracts were immunoblotted to detect the
indicated proteins. b, Immunohistochemical analyses of tumours
from EGFR delE746_A750/T790M mice from a using indicated
antibodies. Scale bar, 50 μm. c, Quantification of TUNEL- and
Ki67-positive cells from tumour nodules (n = 4) from vehicle-
and WZ4002-treated mice. The means and standard deviations are
plotted. *, P < 0.05. d, MRI images of vehicle- or
WZ4002-treated mice at baseline (0 weeks: 0w) and after 2 weeks
(2w) of treatment. e, Quantification of the relative tumour
volume from MRI images from vehicle-treated mice
(E746_A750/T790M (n = 3); L858R/T790M (n = 4)), and
WZ4002-treated L858R/T790M (n = 3) and E746_A750/T790M (n = 3)
mice. The means and standard deviations are plotted. f, Tumours
from vehicle- and WZ4002-treated mice stained with haematoxylin
and eosin. Low-power view (inset) demonstrates near-complete
resolution of tumours in the WZ4002-treated mice. Scale bar, 100
μm.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(2009,
462,
1070-1074)
copyright 2009.
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