Small-molecule inhibitors of cyclin-dependent kinases: molecular tools and potential therapeutics.

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