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PDBsum entry 3k5v
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References listed in PDB file
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Key reference
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Title
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Targeting bcr-Abl by combining allosteric with ATP-Binding-Site inhibitors.
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Authors
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J.Zhang,
F.J.Adrián,
W.Jahnke,
S.W.Cowan-Jacob,
A.G.Li,
R.E.Iacob,
T.Sim,
J.Powers,
C.Dierks,
F.Sun,
G.R.Guo,
Q.Ding,
B.Okram,
Y.Choi,
A.Wojciechowski,
X.Deng,
G.Liu,
G.Fendrich,
A.Strauss,
N.Vajpai,
S.Grzesiek,
T.Tuntland,
Y.Liu,
B.Bursulaya,
M.Azam,
P.W.Manley,
J.R.Engen,
G.Q.Daley,
M.Warmuth,
N.S.Gray.
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Ref.
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Nature, 2010,
463,
501-506.
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PubMed id
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Abstract
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In an effort to find new pharmacological modalities to overcome resistance to
ATP-binding-site inhibitors of Bcr-Abl, we recently reported the discovery of
GNF-2, a selective allosteric Bcr-Abl inhibitor. Here, using solution NMR, X-ray
crystallography, mutagenesis and hydrogen exchange mass spectrometry, we show
that GNF-2 binds to the myristate-binding site of Abl, leading to changes in the
structural dynamics of the ATP-binding site. GNF-5, an analogue of GNF-2 with
improved pharmacokinetic properties, when used in combination with the
ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of
resistance mutations in vitro, displayed additive inhibitory activity in
biochemical and cellular assays against T315I mutant human Bcr-Abl and displayed
in vivo efficacy against this recalcitrant mutant in a murine bone-marrow
transplantation model. These results show that therapeutically relevant
inhibition of Bcr-Abl activity can be achieved with inhibitors that bind to the
myristate-binding site and that combining allosteric and ATP-competitive
inhibitors can overcome resistance to either agent alone.
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