4-Arylazo-3,5-diamino-1H-pyrazole CDK Inhibitors:  SAR Study, Crystal Structure in Complex with CDK2, Selectivity, and Cellular Effects

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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2006-11, Vol.49 (22), p.6500-6509
Main Authors: Kryštof, Vladimír, Cankař, Petr, Fryšová, Iveta, Slouka, Jan, Kontopidis, George, Džubák, Petr, Hajdúch, Marián, Srovnal, Josef, de Azevedo, Walter F, Orság, Martin, Paprskářová, Martina, Rolčík, Jakub, Látr, Aleš, Fischer, Peter M, Strnad, Miroslav
Format: Article
Language:English
Subjects:
Antimetabolites
Antineoplastic agents
Azo Compounds - chemical synthesis
Azo Compounds - pharmacology
Biological and medical sciences
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
Enzyme Inhibitors - pharmacology
General aspects
Humans
Immunoblotting
Medical sciences
Models, Molecular
Pharmacology. Drug treatments
Pyrazoles - chemical synthesis
Pyrazoles - pharmacology
Reverse Transcriptase Polymerase Chain Reaction
Reverse Transcription - drug effects
RNA - biosynthesis
RNA - isolation & purification
Structure-Activity Relationship
Substrate Specificity
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0605740