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-depent 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 ere 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) as 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 compound,, 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. (C) 2002 Elsevier Science Ltd. All rights reserved.