Abstract |
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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Authors | Vladimír Krystof, Petr Cankar, Iveta Frysová, Jan Slouka, George Kontopidis, Petr Dzubák, Marián Hajdúch, Josef Srovnal, Walter F de Azevedo Jr, Martin Orság, Martina Paprskárová, Jakub Rolcík, Ales Látr, Peter M Fischer, Miroslav Strnad |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 49
Issue 22
Pg. 6500-9
(Nov 02 2006)
ISSN: 0022-2623 [Print] United States |
PMID | 17064068
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antimetabolites
- Azo Compounds
- Enzyme Inhibitors
- Pyrazoles
- RNA
- Cyclin-Dependent Kinase 2
- Cyclin-Dependent Kinases
- Bromodeoxyuridine
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Topics |
- Antimetabolites
- Azo Compounds
(chemical synthesis, pharmacology)
- Bromodeoxyuridine
- Cell Cycle
(drug effects)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Crystallography, X-Ray
- Cyclin-Dependent Kinase 2
(antagonists & inhibitors)
- Cyclin-Dependent Kinases
(antagonists & inhibitors)
- Enzyme Inhibitors
(chemical synthesis, pharmacology)
- Humans
- Immunoblotting
- Models, Molecular
- Pyrazoles
(chemical synthesis, pharmacology)
- RNA
(biosynthesis, isolation & purification)
- Reverse Transcriptase Polymerase Chain Reaction
- Reverse Transcription
(drug effects)
- Structure-Activity Relationship
- Substrate Specificity
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