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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.

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.
AuthorsVladimír 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
JournalJournal of medicinal chemistry (J Med Chem) Vol. 49 Issue 22 Pg. 6500-9 (Nov 02 2006) ISSN: 0022-2623 [Print] United States
PMID17064068 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antimetabolites
  • Azo Compounds
  • Enzyme Inhibitors
  • Pyrazoles
  • RNA
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases
  • Bromodeoxyuridine
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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