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PDBsum entry 2bdf
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References listed in PDB file
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Key reference
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Title
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Structural basis of src tyrosine kinase inhibition with a new class of potent and selective trisubstituted purine-Based compounds.
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Authors
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D.Dalgarno,
T.Stehle,
S.Narula,
P.Schelling,
M.R.Van schravendijk,
S.Adams,
L.Andrade,
J.Keats,
M.Ram,
L.Jin,
T.Grossman,
I.Macneil,
C.Metcalf,
W.Shakespeare,
Y.Wang,
T.Keenan,
R.Sundaramoorthi,
R.Bohacek,
M.Weigele,
T.Sawyer.
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Ref.
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Chem Biol Drug Des, 2006,
67,
46-57.
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PubMed id
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Abstract
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The tyrosine kinase pp60src (Src) is the prototypical member of a family of
proteins that participate in a broad array of cellular signal transduction
processes, including cell growth, differentiation, survival, adhesion, and
migration. Abnormal Src family kinase (SFK) signaling has been linked to several
disease states, including osteoporosis and cancer metastases. Src has thus
emerged as a molecular target for the discovery of small-molecule inhibitors
that regulate Src kinase activity by binding to the ATP pocket within the
catalytic domain. Here, we present crystal structures of the kinase domain of
Src in complex with two purine-based inhibitors: AP23451, a small-molecule
inhibitor designed to inhibit Src-dependent bone resorption, and AP23464, a
small-molecule inhibitor designed to inhibit the Src-dependent metastatic spread
of cancer. In each case, a trisubstituted purine template core was elaborated
using structure-based drug design to yield a potent Src kinase inhibitor. These
structures represent early examples of high affinity purine-based Src family
kinase-inhibitor complexes, and they provide a detailed view of the specific
protein-ligand interactions that lead to potent inhibition of Src. In
particular, the 3-hydroxyphenethyl N9 substituent of AP23464 forms unique
interactions with the protein that are critical to the picomolar affinity of
this compound for Src. The comparison of these new structures with two relevant
kinase-inhibitor complexes provides a structural basis for the observed kinase
inhibitory selectivity. Further comparisons reveal a concerted induced-fit
movement between the N- and C-terminal lobes of the kinase that correlates with
the affinity of the ligand. Binding of the most potent inhibitor, AP23464,
results in the largest induced-fit movement, which can be directly linked to
interactions of the hydrophenethyl N9 substituent with a region at the interface
between the two lobes. A less pronounced induced-fit movement is also observed
in the Src-AP23451 complex. These new structures illustrate how the combination
of structural, computational, and medicinal chemistry can be used to rationalize
the process of developing high affinity, selective tyrosine kinase inhibitors as
potential therapeutic agents.
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