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PDBsum entry 4ibm
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Transferase/transferase inhibitor
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PDB id
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4ibm
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References listed in PDB file
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Key reference
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Title
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A highly selective dual insulin receptor (ir)/insulin-Like growth factor 1 receptor (igf-1r) inhibitor derived from an extracellular signal-Regulated kinase (erk) inhibitor.
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Authors
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T.Anastassiadis,
K.C.Duong-Ly,
S.W.Deacon,
A.Lafontant,
H.Ma,
K.Devarajan,
R.L.Dunbrack,
J.Wu,
J.R.Peterson.
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Ref.
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J Biol Chem, 2013,
288,
28068-28077.
[DOI no: ]
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PubMed id
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Abstract
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Dual inhibitors of the closely related receptor tyrosine kinases insulin-like
growth factor 1 receptor (IGF-1R) and insulin receptor (IR) are promising
therapeutic agents in cancer. Here, we report an unusually selective class of
dual inhibitors of IGF-1R and IR identified in a parallel screen of known kinase
inhibitors against a panel of 300 human protein kinases. Biochemical and
structural studies indicate that this class achieves its high selectivity by
binding to the ATP-binding pocket of inactive, unphosphorylated IGF-1R/IR and
stabilizing the activation loop in a native-like inactive conformation. One
member of this compound family was originally reported as an inhibitor of the
serine/threonine kinase ERK, a kinase that is distinct in the structure of its
unphosphorylated/inactive form from IR/IGF-1R. Remarkably, this compound binds
to the ATP-binding pocket of ERK in an entirely different conformation to that
of IGF-1R/IR, explaining the potency against these two structurally distinct
kinase families. These findings suggest a novel approach to polypharmacology in
which two or more unrelated kinases are inhibited by a single compound that
targets different conformations of each target kinase.
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