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PDBsum entry 2a0c
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References listed in PDB file
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Key reference
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Title
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Antiproliferative activity of olomoucine ii, A novel 2,6,9-Trisubstituted purine cyclin-Dependent kinase inhibitor.
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Authors
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V.Krystof,
I.W.Mcnae,
M.D.Walkinshaw,
P.M.Fischer,
P.Müller,
B.Vojtesek,
M.Orság,
L.Havlícek,
M.Strnad.
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Ref.
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Cell Mol Life Sci, 2005,
62,
1763-1771.
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PubMed id
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Abstract
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The study describes the protein kinase selectivity profile, as well as the
binding mode of olomoucine II in the catalytic cleft of CDK2, as determined from
cocrystal analysis. Apart from the main cell cycle-regulating kinase CDK2,
olomoucine II exerts specificity for CDK7 and CDK9, with important functions in
the regulation of RNA transcription. In vitro anticancer activity of the
inhibitor in a panel of tumor cell lines shows a wide potency range with a
slight preference for cells harboring a wild-type p53 gene. Cell-based assays
confirmed activation of p53 protein levels and events leading to accumulation of
p21(WAF1). Additionally, in olomoucine II-treated cells, Mdm2 was found to form
a complex with the ribosomal protein L11, which inhibits Mdm2 ubiquitin ligase
function. We conclude that perturbations in RNA synthesis may lead to activation
of p53 and that this contributes to the antiproliferative potency of
cyclindependent kinase inhibitors.
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