Pyrazolo[3,4-b]quinoxalines. A new class of cyclin-dependent kinases inhibitors.
Protein kinases are involved in most physiological processes and in numerous diseases. Therefore, inhibitors of protein kinases have therefore a wide therapeutic potential. While screening for inhibitors of cyclin-dependent kinases (CDK's) and glycogen synthase kinase-3 (GSK-3), we identified pyrazolo[3,4-b]quinoxalines as sub-micromolar inhibitors of CDK1/cyclin B. A preliminary structure-activity relationship study suggests that this family of compounds can be optimized to inhibit CDK's and GSK-3. Compounds were tested for their anti-proliferative activity and the results show that several of them displayed a significant inhibitory effect on CDK1/cyclin B. The most active compound (1) was also tested against the brain kinases CDK5/p25 and GSK-3, and proved to be a good inhibitor of both of them. On the contrary, none of the compounds showed any activity in the CDC25 phosphatase assay. As an additional approach, affinity chromatography on immobilized pyrazolo[3,4-b]quinoxalines will be used to identify the intracellular targets of this family of compounds.
Ortega
Miguel A
MA
Unidad en Investigación y Desarrollo de Medicamentos, Centro de Investigación en Farmacobiología Aplicada, Universidad de Navarra, E-31080 Pamplona, Spain.
Montoya
María E
ME
Zarranz
Belén
B
Jaso
Andrés
A
Aldana
Ignacio
I
Leclerc
Sophie
S
Meijer
Laurent
L
Monge
Antonio
A
D000595:Amino Acid Sequence; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D011720:Pyrazoles / Q000737:chemistry*; D011810:Quinoxalines / Q000737:chemistry / Q000494:pharmacology*; D013055:Spectrophotometry, Infrared
D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011810:Quinoxalines; D018844:Cyclin-Dependent Kinases