ATP-noncompetitive CDK inhibitors for cancer therapy: an overview.

INTRODUCTION: Cyclin-dependent kinases (CDKs) are the key drivers of cell cycle progression and are often deregulated in cancer, therefore, targeting CDKs has long been pursued as a therapeutic strategy to tackle cancer. Unfortunately, however, none of the first-generation CDK inhibitors has yielded the expected efficacy to be successfully translated to the clinic mostly because, by targeting the very conserved kinase ATP-binding site resulted to be poorly specific and quite toxic. AREAS COVERED: Here, the authors review recent approaches aimed at developing more specific CDK inhibitors mostly through the aid of computational drug design studies and report various small molecules and peptides, which resulted in promising CDK ATP-noncompetitive inhibitors. EXPERT OPINION: Despite few successes, these new approaches still need additional considerations to generate effective antitumoral agents. The authors discuss some of the hurdles to overcome for a successful clinical translation.