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PDBsum entry 3cs9
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References listed in PDB file
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Key reference
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Title
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Characterization of amn107, A selective inhibitor of native and mutant bcr-Abl.
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Authors
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E.Weisberg,
P.W.Manley,
W.Breitenstein,
J.Brüggen,
S.W.Cowan-Jacob,
A.Ray,
B.Huntly,
D.Fabbro,
G.Fendrich,
E.Hall-Meyers,
A.L.Kung,
J.Mestan,
G.Q.Daley,
L.Callahan,
L.Catley,
C.Cavazza,
M.Azam,
A.Mohammed,
D.Neuberg,
R.D.Wright,
D.G.Gilliland,
J.D.Griffin.
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Ref.
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Cancer Cell, 2005,
7,
129-141.
[DOI no: ]
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PubMed id
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Abstract
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The Bcr-Abl tyrosine kinase oncogene causes chronic myelogenous leukemia (CML)
and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).
We describe a novel selective inhibitor of Bcr-Abl, AMN107 (IC50 <30 nM),
which is significantly more potent than imatinib, and active against a number of
imatinib-resistant Bcr-Abl mutants. Crystallographic analysis of Abl-AMN107
complexes provides a structural explanation for the differential activity of
AMN107 and imatinib against imatinib-resistant Bcr-Abl. Consistent with its in
vitro and pharmacokinetic profile, AMN107 prolonged survival of mice injected
with Bcr-Abl-transformed hematopoietic cell lines or primary marrow cells, and
prolonged survival in imatinib-resistant CML mouse models. AMN107 is a promising
new inhibitor for the therapy of CML and Ph+ ALL.
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Figure 3.
Figure 3. Abl-AMN107 complex
A: Superposition of AMN107
(magenta) bound to Abl^M351T (orange), and imatinib (green)
bound to Abl (yellow). H bonds within the AMN107-Abl^M351T
complex are depicted as dashed red lines, whereas those in the
imatinib complex are shown in black. The variability in the
positions of side chains from the C-helix (top right corner) is
due to crystal contacts that influence the position of the
N-terminal lobe of the kinase. The methyl-imidazole group of
AMN107 packs in a hydrophobic pocket formed by these residues
with the nitrogen exposed to solvent.
B: Superposition of
parts of the backbone structures of imatinib-Abl (yellow),
AMN107-Abl^M351T (orange), and AMN107-Abl (cyan). The inhibitors
are shown in green, magenta and blue, respectively. The small
black arrows show the shifts within helix E and the preceding
loop, DE. Figure 3. Abl-AMN107 complexA: Superposition of
AMN107 (magenta) bound to Abl^M351T (orange), and imatinib
(green) bound to Abl (yellow). H bonds within the
AMN107-Abl^M351T complex are depicted as dashed red lines,
whereas those in the imatinib complex are shown in black. The
variability in the positions of side chains from the C-helix
(top right corner) is due to crystal contacts that influence the
position of the N-terminal lobe of the kinase. The
methyl-imidazole group of AMN107 packs in a hydrophobic pocket
formed by these residues with the nitrogen exposed to solvent.B:
Superposition of parts of the backbone structures of
imatinib-Abl (yellow), AMN107-Abl^M351T (orange), and AMN107-Abl
(cyan). The inhibitors are shown in green, magenta and blue,
respectively. The small black arrows show the shifts within
helix E and the preceding loop, DE.
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Figure 5.
Figure 5. Efficacy of AMN107 against 32D.p210- and
32D-E255V-Luc+ cells in vivo
Left panel: Bioluminescence of
vehicle- or AMN107-treated mice. Right panel: Quantitation of
AMN107 effects against 32D.p210-Luc+ cells in vivo. Bars are
SEM, n = 5. Figure 5. Efficacy of AMN107 against 32D.p210-
and 32D-E255V-Luc+ cells in vivoLeft panel: Bioluminescence of
vehicle- or AMN107-treated mice. Right panel: Quantitation of
AMN107 effects against 32D.p210-Luc+ cells in vivo. Bars are
SEM, n = 5.
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The above figures are
reprinted
by permission from Cell Press:
Cancer Cell
(2005,
7,
129-141)
copyright 2005.
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Secondary reference #1
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Title
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Solution conformations and dynamics of abl kinase inhibitor complexes determined by nmr substantiate the different binding modes of imatinib/nilotinib and dasatinib
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Authors
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N.Vajpai,
A.Strauss,
G.Fendrich,
S.W.Cowan-Jacob,
P.W.Manley,
S.Grzesiek,
W.Jahnke.
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Ref.
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TO BE PUBLISHED ...
[DOI no: ]
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PubMed id
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Note: In the PDB file this reference is
annotated as "TO BE PUBLISHED". The citation details given above have
been manually determined.
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