Inhibitors of cyclin-dependent kinases as anti-cancer therapeutics

Initiation, progression, and completion of the cell cycle are regulated by various cyclin-dependent kinases (CDKs), which are thus critical for cell g rowth. Tumour development is closely associated with genetic alteration and deregulation of CDKs and their regulators, suggesting that inhibitors of C DKs may be useful anti-cancer therapeutics. Indeed, early results suggest t hat transformed and normal cells differ in their requirement for e.g. cycli n/CDK2 and that it may be possible to develop novel antineoplastic agents d evoid of the general host toxicity observed with conventional cystostatic d rugs. Numerous active-site inhibitors of CDKs have been studied; the main l imitation with these ATP antagonists is kinase specificity for CDKs. Howeve r, screening of compound collections, as well as rational design based on e nzyme-ligand complex crystal structures, are now yielding pre-clinical cand idates, particularly certain purine and flavonoid analogues, with impressiv e potency and selectivity. Natural CDK inhibitors (CKIs), e.g. the tumour s uppressor gene products p16(INK4), P21(WAF1), and p27(KIP1), form the start ing point for the design of mechanism-based CDK inhibitors. A number of the se small proteins have been dissected and inhibitory lead peptides amenable to peptidomimetic development have been identified. Conversion of these pe ptides into pharmaceutically useful molecules is greatly aided by the recen t elucidation of CKI/CDK crystal and solution structures. Additional intera ction sites on CDKs being exploited for the purposes of inhibitor design in clude: phosphorylation/dephosphorylation sites, macromolecular substrate bi nding site, CKS regulatory subunit binding sites, cyclin-binding site, cell ular localisation domain, and destruction box. Finally, progress has recent ly been made in the application of antisense technology in order to target CDK activity.