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PDBsum entry 4ckr
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References listed in PDB file
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Key reference
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Title
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Discovery of a potent and selective ddr1 receptor tyrosine kinase inhibitor.
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Authors
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H.G.Kim,
L.Tan,
E.L.Weisberg,
F.Liu,
P.Canning,
H.G.Choi,
S.A.Ezell,
H.Wu,
Z.Zhao,
J.Wang,
A.Mandinova,
J.D.Griffin,
A.N.Bullock,
Q.Liu,
S.W.Lee,
N.S.Gray.
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Ref.
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Acs Chem Biol, 2013,
8,
2145-2150.
[DOI no: ]
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PubMed id
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Abstract
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The DDR1 receptor tyrosine kinase is activated by matrix collagens and has been
implicated in numerous cellular functions such as proliferation,
differentiation, adhesion, migration, and invasion. Here we report the discovery
of a potent and selective DDR1 inhibitor, DDR1-IN-1, and present the 2.2 Å DDR1
co-crystal structure. DDR1-IN-1 binds to DDR1 in the 'DFG-out' conformation and
inhibits DDR1 autophosphorylation in cells at submicromolar concentrations with
good selectivity as assessed against a panel of 451 kinases measured using the
KinomeScan technology. We identified a mutation in the hinge region of DDR1,
G707A, that confers >20-fold resistance to the ability of DDR1-IN-1 to
inhibit DDR1 autophosphorylation and can be used to establish what pharmacology
is DDR1-dependent. A combinatorial screen of DDR1-IN-1 with a library of
annotated kinase inhibitors revealed that inhibitors of PI3K and mTOR such as
GSK2126458 potentiate the antiproliferative activity of DDR1-IN-1 in colorectal
cancer cell lines. DDR1-IN-1 provides a useful pharmacological probe for
DDR1-dependent signal transduction.
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