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PDBsum entry 2vu3
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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 n-(4-Piperidinyl)-4-(2,6-Dichlorobenzoylamino)-1h-Pyrazole-3-Carboxamide (at7519), A novel cyclin dependent kinase inhibitor using fragment-Based x-Ray crystallography and structure based drug design.
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Authors
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P.G.Wyatt,
A.J.Woodhead,
V.Berdini,
J.A.Boulstridge,
M.G.Carr,
D.M.Cross,
D.J.Davis,
L.A.Devine,
T.R.Early,
R.E.Feltell,
E.J.Lewis,
R.L.Mcmenamin,
E.F.Navarro,
M.A.O'Brien,
M.O'Reilly,
M.Reule,
G.Saxty,
L.C.Seavers,
D.M.Smith,
M.S.Squires,
G.Trewartha,
M.T.Walker,
A.J.Woolford.
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Ref.
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J Med Chem, 2008,
51,
4986-4999.
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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
percentage match of
93%.
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Abstract
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The application of fragment-based screening techniques to cyclin dependent
kinase 2 (CDK2) identified multiple (>30) efficient, synthetically tractable
small molecule hits for further optimization. Structure-based design approaches
led to the identification of multiple lead series, which retained the key
interactions of the initial binding fragments and additionally explored other
areas of the ATP binding site. The majority of this paper details the
structure-guided optimization of indazole (6) using information gained from
multiple ligand-CDK2 cocrystal structures. Identification of key binding
features for this class of compounds resulted in a series of molecules with low
nM affinity for CDK2. Optimisation of cellular activity and characterization of
pharmacokinetic properties led to the identification of 33 (AT7519), which is
currently being evaluated in clinical trials for the treatment of human cancers.
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