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PDBsum entry 3f3w
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References listed in PDB file
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Key reference
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Title
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Hybrid compound design to overcome the gatekeeper t338m mutation in csrc.
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Authors
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M.Getlik,
C.Grütter,
J.R.Simard,
S.Klüter,
M.Rabiller,
H.B.Rode,
A.Robubi,
D.Rauh.
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Ref.
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J Med Chem, 2009,
52,
3915-3926.
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PubMed id
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Abstract
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The emergence of drug resistance remains a fundamental challenge in the
development of kinase inhibitors that are effective over long-term treatments.
Allosteric inhibitors that bind to sites lying outside the highly conserved ATP
pocket are thought to be more selective than ATP-competitive inhibitors and may
circumvent some mechanisms of drug resistance. Crystal structures of type I and
allosteric type III inhibitors in complex with the tyrosine kinase cSrc allowed
us to employ principles of structure-based design to develop these scaffolds
into potent type II kinase inhibitors. One of these compounds, 3c (RL46),
disrupts FAK-mediated focal adhesions in cancer cells via direct inhibition of
cSrc. Details gleaned from crystal structures revealed a key feature of a subset
of these compounds, a surprising flexibility in the vicinity of the gatekeeper
residue that allows these compounds to overcome a dasatinib-resistant gatekeeper
mutation emerging in cSrc.
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