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PDBsum entry 3g6g
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References listed in PDB file
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Key reference
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Title
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Equally potent inhibition of c-Src and abl by compounds that recognize inactive kinase conformations.
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Authors
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M.A.Seeliger,
P.Ranjitkar,
C.Kasap,
Y.Shan,
D.E.Shaw,
N.P.Shah,
J.Kuriyan,
D.J.Maly.
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Ref.
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Cancer Res, 2009,
69,
2384-2392.
[DOI no: ]
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PubMed id
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Abstract
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Imatinib is an inhibitor of the Abl tyrosine kinase domain that is effective in
the treatment of chronic myelogenic leukemia. Although imatinib binds tightly to
the Abl kinase domain, its affinity for the closely related kinase domain of
c-Src is at least 2,000-fold lower. Imatinib recognition requires a specific
inactive conformation of the kinase domain, in which a conserved Asp-Phe-Gly
(DFG) motif is flipped with respect to the active conformation. The inability of
c-Src to readily adopt this flipped DFG conformation was thought to underlie the
selectivity of imatinib for Abl over c-Src. Here, we present a series of
inhibitors (DSA compounds) that are based on the core scaffold of imatinib but
which bind with equally high potency to c-Src and Abl. The DSA compounds bind to
c-Src in the DFG-flipped conformation, as confirmed by crystal structures and
kinetic analysis. The origin of the high affinity of these compounds for c-Src
is suggested by the fact that they also inhibit clinically relevant Abl variants
bearing mutations in a structural element, the P-loop, that normally interacts
with the phosphate groups of ATP but is folded over a substructure of imatinib
in Abl. Importantly, several of the DSA compounds block the growth of Ba/F3
cells harboring imatinib-resistant BCR-ABL mutants, including the Thr315Ile
"gatekeeper" mutation, but do not suppress the growth of parental Ba/F3 cells.
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