CDK2 Allosteric Modulators: The New Route in the Design of New Drugs as Anticancer and Non-hormonal Contraceptives

CDK2 plays a pivotal role in controlling the cell cycle progression in eukaryotes and for this reason, it has been the subject of several studies for suitable inhibitors in the last decades. But more than 30 years of basic research have not generated an inhibitor as marketed drugs. Some inhibitors are to date in early phase clinical development. Moreover, most efforts to develop CDK2 inhibitors have been oriented towards orthosteric inhibitors, which block the kinase activity by binding to the ATP binding site, competing directly with ATP. These compounds have off-target kinase activity, because of the structural homology of the active sites of several other kinases. Targeting the CDK2 allosteric binding pocket could produce successful CDK2 inhibitors. Few examples of high-affinity allosteric CDK2 inhibitors are known. Despite promising research results, none has been approved for marketing. In recent years, various methodologies have been reported capable of identifying new and never-discovered portions of the target protein, which present adequate druggability characteristics. In this paper, we have highlighted and discussed the more recent findings on allosteric inhibitors intending to encouraging further exploration mainly focused on in silico drug discovery.