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PDBsum entry 2clx
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References listed in PDB file
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Key reference
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Title
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4-Arylazo-3,5-Diamino-1h-Pyrazole cdk inhibitors: sar study, Crystal structure in complex with cdk2, Selectivity, And cellular effects.
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Authors
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V.Krystof,
P.Cankar,
I.Frysová,
J.Slouka,
G.Kontopidis,
P.Dzubák,
M.Hajdúch,
J.Srovnal,
W.F.De azevedo,
M.Orság,
M.Paprskárová,
J.Rolcík,
A.Látr,
P.M.Fischer,
M.Strnad.
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Ref.
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J Med Chem, 2006,
49,
6500-6509.
[DOI no: ]
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PubMed id
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Abstract
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In a routine screening of our small-molecule compound collection we recently
identified 4-arylazo-3,5-diamino-1H-pyrazoles as a novel group of ATP
antagonists with moderate potency against CDK2-cyclin E. A preliminary SAR study
based on 35 analogues suggests ways in which the pharmacophore could be further
optimized, for example, via substitutions in the 4-aryl ring. Enzyme kinetics
studies with the lead compound and X-ray crystallography of an inhibitor-CDK2
complex demonstrated that its mode of inhibition is competitive. Functional
kinase assays confirmed the selectivity toward CDKs, with a preference for
CDK9-cyclin T1. The most potent inhibitor,
4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol 31b (CAN508), reduced the
frequency of S-phase cells of the cancer cell line HT-29 in antiproliferation
assays. Further observed cellular effects included decreased phosphorylation of
the retinoblastoma protein and the C-terminal domain of RNA polymerase II,
inhibition of mRNA synthesis, and induction of the tumor suppressor protein p53,
all of which are consistent with inhibition of CDK9.
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