ABSTRACT
In 1995 the Dupont Merck Pharmaceutical Co., later the Dupont Pharmaceutical Co., entered into a collaboration with Mitotix to research a series of cyclin-dependent kinase (CDK) inhibitors for use as anticancer agents. Initially we were interested in selective inhibitors of CDK4/cyclinD1 (CDK4/D1), but we later expanded our focus to include selective inhibitors of CDK2/cyclinE (CDK2/E) as well as balanced inhibitors of both of these CDKs. High-throughput screening of our compound collection against CDK4/D1 afforded a series of hits. One of the most interesting of these leads proved to be the indenopyrazole
13.1
(Table 13.1). As described in the following text, the development of this lead has produced a series of highly potent and selective CDK inhibitors with
in vitro
and
in vivo
efficacy as anticancer agents.
