Chemical Proteomics and Characterization of [1,3,6]-Trisubstituted-pyrazolo[3,4-d]-pyrimidin-4-ones: A Novel Class of Selective Cdk/Crk Inhibitors

Proc Amer Assoc Cancer Res, Volume 47, 2006 1543 [1,3,6]-trisubstituted-pyrazolo[3,4-d]-pyrimidin-4-ones constitute a novel class of potent inhibitors of cyclin dependent kinases (CDKs) [1, 2]. Here, we describe the application of three-hybrid proteome scanning methodologies to the characterization of the target spectrum and biological activities of select compounds of this chemical class. These compounds were found to exhibit a remarkable selectivity for a subset of CDKs and CDK-related kinases (CRKs). The CDK/CRK target spectra varied significantly among various analogs, indicating that the [1,3,6]-trisubstituted-pyrazolo[3,4-d]-pyrimidin-4-one chemical scaffold provides a unique platform for the design and optimization of compounds with potentially diverse therapeutic applications, including compounds with potent apoptosis-inducing anticancer activities. 1. Markwalder, J.A et al. (2004). Synthesis and biological evaluation of 1-aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one inhibitors of cyclin-dependent kinases. J Med Chem 47 , 5894-5911. 2. Caligiuri, M et al. (2005). A Proteome-Wide CDK/CRK-Specific Kinase Inhibitor Promotes Tumor Cell Death in the Absence of Cell Cycle Progression. Chem Biol 12 , 1103-1115.