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PDBsum entry 4byj
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References listed in PDB file
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Key reference
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Title
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Aurora isoform selectivity: design and synthesis of imidazo[4,5-B]pyridine derivatives as highly selective inhibitors of aurora-A kinase in cells.
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Authors
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V.Bavetsias,
A.Faisal,
S.Crumpler,
N.Brown,
M.Kosmopoulou,
A.Joshi,
B.Atrash,
Y.Pérez-Fuertes,
J.A.Schmitt,
K.J.Boxall,
R.Burke,
C.Sun,
S.Avery,
K.Bush,
A.Henley,
F.I.Raynaud,
P.Workman,
R.Bayliss,
S.Linardopoulos,
J.Blagg.
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Ref.
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J Med Chem, 2013,
56,
9122-9135.
[DOI no: ]
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PubMed id
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Abstract
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Aurora-A differs from Aurora-B/C at three positions in the ATP-binding pocket
(L215, T217, and R220). Exploiting these differences, crystal structures of
ligand-Aurora protein interactions formed the basis of a design principle for
imidazo[4,5-b]pyridine-derived Aurora-A-selective inhibitors. Guided by a
computational modeling approach, appropriate C7-imidazo[4,5-b]pyridine
derivatization led to the discovery of highly selective inhibitors, such as
compound 28c, of Aurora-A over Aurora-B. In HCT116 human colon carcinoma cells,
28c and 40f inhibited the Aurora-A L215R and R220K mutants with IC50 values
similar to those seen for the Aurora-A wild type. However, the Aurora-A T217E
mutant was significantly less sensitive to inhibition by 28c and 40f compared to
the Aurora-A wild type, suggesting that the T217 residue plays a critical role
in governing the observed isoform selectivity for Aurora-A inhibition. These
compounds are useful small-molecule chemical tools to further explore the
function of Aurora-A in cells.
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