Small-Molecule Inhibitors of Cyclin-Dependent Kinases: Molecular Tools and Potential Therapeutics

Abstract

The cell has evolved a number of distinct ways to regulate cyclin-dependent kinases (CDKs). These include both activating steps (phosphorylation at T161, binding of a cyclin) and inhibitory ones (phosphorylation of T14, Y15, binding of a protein inhibitor, and ubiquitin-mediated proteolysis of the cyclin subunit). All represent potential points of intervention for the design of small-molecule inhibitors. Thus, in theory, it will be possible to identify inhibitors of CDK activity which act though a number of different mechanisms, i.e., competition for substrates (ATP and peptide/ protein), competition for cyclin binding, mimicking of CDK-inhibitory proteins, or stimulation of specific cyclin destruction. In practice, however, things are not so simple. In order for a small molecule to penetrate the cell membrane, it typically has to be of small size (e.g., M _r < 500). With such size constraints, the highest likelihood is that such a small molecule will bind most tightly in small, defined pockets in the target protein, such as the ATP-binding pocket. The potential for disruption of a large protein—protein interface, such as a cyclin—CDK-binding surface, is much lower. It is therefore predictable that the majority of small molecular weight CDK-inhibitory compounds identified to date are ATP competitors. These fall into several major classes, including the purine analogues, the flavonoids, staurosporine analogues, and butyrolactone-1. Despite the fact that these inhibitors currently are either nonselective or low in potency, they all present potential starting points for the identification of highly potent, specific CDK inhibitors. The structures of these inhibitors are shown in Fig. 1 and they are described in more detail below.