Pyrazolopyridazine 1a was identified in a high-throughput screening carried out by BASFBioresearch Corp. (Worcester, MA) as a potent inhibitor of CDK1/cyclin B and shown to haveselectivity for the CDK family. Analogues of the lead compound have been synthesized andtheir antitumor activities have been tested. A molecular model of the complex between thelead compound and the CDK2 ATP binding site has been built using a combination ofconformational search and automated docking techniques. The stability of the resulting complexhas been assessed by molecular dynamics simulations and the experimental results obtainedfor the synthesized analogues have been rationalized on the basis of the proposed binding modefor compound 1a. As a result of the SAR study, monofuryl 1o has been synthesized and is oneof the most active compounds against CDK1 of this series.
