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PDBsum entry 1ke5
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Oxindole-Based inhibitors of cyclin-Dependent kinase 2 (cdk2): design, Synthesis, Enzymatic activities, And x-Ray crystallographic analysis.
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Authors
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H.N.Bramson,
J.Corona,
S.T.Davis,
S.H.Dickerson,
M.Edelstein,
S.V.Frye,
R.T.Gampe,
P.A.Harris,
A.Hassell,
W.D.Holmes,
R.N.Hunter,
K.E.Lackey,
B.Lovejoy,
M.J.Luzzio,
V.Montana,
W.J.Rocque,
D.Rusnak,
L.Shewchuk,
J.M.Veal,
D.H.Walker,
L.F.Kuyper.
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Ref.
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J Med Chem, 2001,
44,
4339-4358.
[DOI no: ]
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PubMed id
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Abstract
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Two closely related classes of oxindole-based compounds, 1H-indole-2,3-dione
3-phenylhydrazones and 3-(anilinomethylene)-1,3-dihydro-2H-indol-2-ones, were
shown to potently inhibit cyclin-dependent kinase 2 (CDK2). The initial lead
compound was prepared as a homologue of the
3-benzylidene-1,3-dihydro-2H-indol-2-one class of kinase inhibitor.
Crystallographic analysis of the lead compound bound to CDK2 provided the basis
for analogue design. A semiautomated method of ligand docking was used to select
compounds for synthesis, and a number of compounds with low nanomolar inhibitory
activity versus CDK2 were identified. Enzyme binding determinants for several
analogues were evaluated by X-ray crystallography. Compounds in this series
inhibited CDK2 with a potency approximately 10-fold greater than that for CDK1.
Members of this class of inhibitor cause an arrest of the cell cycle and have
shown potential utility in the prevention of chemotherapy-induced alopecia.
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