4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects
Language English Country United States Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
17064068
DOI
10.1021/jm0605740
Knihovny.cz E-resources
- MeSH
- Antimetabolites MeSH
- Azo Compounds chemical synthesis pharmacology MeSH
- Bromodeoxyuridine MeSH
- Cell Cycle drug effects MeSH
- Cyclin-Dependent Kinase 2 antagonists & inhibitors MeSH
- Cyclin-Dependent Kinases antagonists & inhibitors MeSH
- Immunoblotting MeSH
- Enzyme Inhibitors chemical synthesis pharmacology MeSH
- Crystallography, X-Ray MeSH
- Humans MeSH
- Models, Molecular MeSH
- Cell Line, Tumor MeSH
- Reverse Transcriptase Polymerase Chain Reaction MeSH
- Cell Proliferation drug effects MeSH
- Pyrazoles chemical synthesis pharmacology MeSH
- Reverse Transcription drug effects MeSH
- RNA biosynthesis isolation & purification MeSH
- Substrate Specificity MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Antimetabolites MeSH
- Azo Compounds MeSH
- Bromodeoxyuridine MeSH
- Cyclin-Dependent Kinase 2 MeSH
- Cyclin-Dependent Kinases MeSH
- Enzyme Inhibitors MeSH
- Pyrazoles MeSH
- RNA MeSH
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.
References provided by Crossref.org
Modification of Boc-Protected CAN508 via Acylation and Suzuki-Miyaura Coupling
Perspective of cyclin-dependent kinase 9 (CDK9) as a drug target
PDB
2CLX
