Pyrazolo[3,4-b]quinoxalines. A new class of cyclin-dependent kinases inhibitors |
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Authors: | Ortega Miguel A Montoya María E Zarranz Belén Jaso Andrés Aldana Ignacio Leclerc Sophie Meijer Laurent Monge Antonio |
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Institution: | Unidad en Investigación y Desarrollo de Medicamentos, Centro de Investigación en Farmacobiología Aplicada, Universidad de Navarra, E-31080 Pamplona, Spain. |
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Abstract: | 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 pyrazolo3,4-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 pyrazolo3,4-b]quinoxalines will be used to identify the intracellular targets of this family of compounds. |
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