Pyrazolo3,4-cpyridazines as Novel and Selective Inhibitors of Cyclin-Dependent Kinases

摘要

Pyrazolopyridazine la was identified in a high-throughput screening carried out by BASF Bioresearch Corp.(Worcester,MA)as a potent inhibitor of CDKl/cyclin B and shown to have selectivity for the CDK family.Analogues of the lead compound have been synthesized and their antitumor activities have been tested.A molecular model of the complex between the lead compound and the CDK2 ATP binding site has been built using a combination of conformational search and automated docking techniques.The stability of the resulting complex has been assessed by molecular dynamics simulations and the experimental results obtained for the synthesized analogues have been rationalized on the basis of the proposed binding mode for compound la.As a result of the SAR study,monofuryl lo has been synthesized and is one of the most active compounds against CDK1 of this series.