Synthesis, SAR and biological evaluation of 1,6-disubstituted-1H-pyrazolo[3,4-d]pyrimidines as dual inhibitors of Aurora kinases and CDK1

Abstract: Since the early 2000s, the Aurora kinases have become major targets of oncology drug discovery particularly Aurora-A and Aurora-B kinases (AKA/AKB) for which the selective inhibition in cells lead to different phenotypes. In addition to targeting these Aurora kinases involved in mitosis, CDK1 has been added as a primary inhibition target in hopes of enhancing the cytotoxicity of our chemotypes harboring the pyrazolopyrimidine core. SAR optimization of this series using the AKA, AKB and CDK1 biochemical assays led to the discovery of the compound 7h which combines strong potency against the 3 kinases with an acceptable microsomal stability. Finally, switching from a primary amide to a two-substituted pyrrolidine amide gave rise to compound 15a which exhibited the desired AKA/CDK1 inhibition phenotype in cells but showed moderate activity in animal models using HCT116 tumor cell lines. [Copyright &y& Elsevier]