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PDBsum entry 3fdn
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References listed in PDB file
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Key reference
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Title
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Structure-Based drug design of novel aurora kinase a inhibitors: structural basis for potency and specificity.
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Authors
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M.S.Coumar,
J.S.Leou,
P.Shukla,
J.S.Wu,
A.K.Dixit,
W.H.Lin,
C.Y.Chang,
T.W.Lien,
U.K.Tan,
C.H.Chen,
J.T.Hsu,
Y.S.Chao,
S.Y.Wu,
H.P.Hsieh.
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Ref.
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J Med Chem, 2009,
52,
1050-1062.
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PubMed id
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Abstract
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Aurora kinases have emerged as attractive targets for the design of anticancer
drugs. Through structure-based virtual screening, novel pyrazole hit 8a was
identified as Aurora kinase A inhibitor (IC(50) = 15.1 microM). X-ray cocrystal
structure of 8a in complex with Aurora A protein revealed the C-4 position ethyl
carboxylate side chain as a possible modification site for improving the
potency. On the basis of this insight, bioisosteric replacement of the ester
with amide linkage and changing the ethyl substituent to hydrophobic
3-acetamidophenyl ring led to the identification of 12w with a approximately
450-fold improved Aurora kinase A inhibition potency (IC(50) = 33 nM), compared
to 8a. Compound 12w showed selective inhibition of Aurora A kinase over Aurora
B/C, which might be due to the presence of a unique H-bond interaction between
the 3-acetamido group and the Aurora A nonconserved Thr217 residue, which in
Aurora B/C is Glu and found to sterically clash with the 3-acetamido group in
modeling studies.
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