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PDBsum entry 2w1h
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References listed in PDB file
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Key reference
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Title
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Fragment-Based discovery of the pyrazol-4-Yl urea (at9283), A multitargeted kinase inhibitor with potent aurora kinase activity.
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Authors
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S.Howard,
V.Berdini,
J.A.Boulstridge,
M.G.Carr,
D.M.Cross,
J.Curry,
L.A.Devine,
T.R.Early,
L.Fazal,
A.L.Gill,
M.Heathcote,
S.Maman,
J.E.Matthews,
R.L.Mcmenamin,
E.F.Navarro,
M.A.O'Brien,
M.O'Reilly,
D.C.Rees,
M.Reule,
D.Tisi,
G.Williams,
M.Vinković,
P.G.Wyatt.
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Ref.
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J Med Chem, 2009,
52,
379-388.
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PubMed id
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Abstract
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Here, we describe the identification of a clinical candidate via structure-based
optimization of a ligand efficient pyrazole-benzimidazole fragment. Aurora
kinases play a key role in the regulation of mitosis and in recent years have
become attractive targets for the treatment of cancer. X-ray crystallographic
structures were generated using a novel soakable form of Aurora A and were used
to drive the optimization toward potent (IC(50) approximately 3 nM) dual Aurora
A/Aurora B inhibitors. These compounds inhibited growth and survival of HCT116
cells and produced the polyploid cellular phenotype typically associated with
Aurora B kinase inhibition. Optimization of cellular activity and
physicochemical properties ultimately led to the identification of compound 16
(AT9283). In addition to Aurora A and Aurora B, compound 16 was also found to
inhibit a number of other kinases including JAK2 and Abl (T315I). This compound
demonstrated in vivo efficacy in mouse xenograft models and is currently under
evaluation in phase I clinical trials.
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