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PDBsum entry 2wms
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References listed in PDB file
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Key reference
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Title
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Identification of inhibitors of checkpoint kinase 1 through template screening.
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Authors
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T.P.Matthews,
S.Klair,
S.Burns,
K.Boxall,
M.Cherry,
M.Fisher,
I.M.Westwood,
M.I.Walton,
T.Mchardy,
K.M.Cheung,
R.Van montfort,
D.Williams,
G.W.Aherne,
M.D.Garrett,
J.Reader,
I.Collins.
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Ref.
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J Med Chem, 2009,
52,
4810-4819.
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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 were identified by an automated
search of PubMed on title and author
names, giving a
perfect match.
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Abstract
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Checkpoint kinase 1 (CHK1) is an oncology target of significant current
interest. Inhibition of CHK1 abrogates DNA damage-induced cell cycle checkpoints
and sensitizes p53 deficient cancer cells to genotoxic therapies. Using template
screening, a fragment-based approach to small molecule hit generation, we have
identified multiple CHK1 inhibitor scaffolds suitable for further optimization.
The sequential combination of in silico low molecular weight template selection,
a high concentration biochemical assay and hit validation through protein-ligand
X-ray crystallography provided 13 template hits from an initial in silico
screening library of ca. 15000 compounds. The use of appropriate
counter-screening to rule out nonspecific aggregation by test compounds was
essential for optimum performance of the high concentration bioassay. One low
molecular weight, weakly active purine template hit was progressed by iterative
structure-based design to give submicromolar pyrazolopyridines with good ligand
efficiency and appropriate CHK1-mediated cellular activity in HT29 colon cancer
cells.
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