Recent advances on structure-informed drug discovery of cyclin-dependent kinase-2 inhibitors.

Serine and threonine kinases play an important role in signal-transduction pathways. Within this kinase family, cyclin-dependent kinase (CDK)2 is an attractive target for oncology involved in cell cycle regulation. In recent years, kinase inhibition has become a major area for therapeutic involvement. As we discuss here, these efforts have resulted in a considerable increase in the number of available high-resolution structures of CDK2-inhibitor complexes. A large amount of structural-based and computational work has allowed the identification of novel chemical scaffolds and structural motifs to design potent CDK2 inhibitors. Of any kinase, CDK2 has the most structures available from the protein databank, averaging 22 new structures per year since 2002. A protein-ligand interaction fingerprint analysis of the available CDK2 protein-ligand complexes indicates that structural diversity is attainable from the structure-based design of CDK2 inhibitors. Since the first CDK2 structure was published in 1996, seven new chemical entities (NCEs) have been advanced to clinical stages. To date, only three of these NCEs have had their complexes published in the protein databank. This review summarizes the structurally informed efforts in the field of CDK2 inhibitor design.