Inhibitors of Cyclin-Dependent Kinases as Anti-Cancer Therapeutics

Abstract

Initiation, progression, and completion of the cell cycle are regulated by various cyclin-dependent kinases (CDKs), which are thus critical for cell growth. Tumour development is closely associated with genetic alteration and deregulation of CDKs and their regulators, suggesting that inhibitors of CDKs may be useful anticancer therapeutics. Indeed, early results suggest that transformed and normal cells differ in their requirement for e.g. cyclin/CDK2 and that it may be possible to develop novel antineoplastic agents devoid of the general host toxicity observed with conventional cystostatic drugs. Numerous active-site inhibitors of CDKs have been studied; the main limitation with these ATP antagonists is kinase specificity for CDKs. However, screening of compound collections, as well as rational design based on enzyme-ligand complex crystal structures, are now yielding pre-clinical candidates, particularly certain purine and flavonoid analogues, with impressive potency and selectivity. Natural CDK inhibitors (CKIs), e.g. the tumour suppressor gene products p16 INK4 , p21 WAF1 , and p27 KIP1 , form the starting point for the design of mechanism-based CDK inhibitors. A number of these small proteins have been dissected and inhibitory lead peptides amenable to peptidomimetic development have been identified. Conversion of these peptides into pharmaceutically useful molecules is greatly aided by the recent elucidation of CKI/CDK crystal and solution structures. Additional interaction sites on CDKs being exploited for the purposes of inhibitor design include: phosphorylation/dephosphorylation sites, macromolecular substrate binding site, CKS regulatory subunit binding sites, cyclin-binding site, cellular localisation domain, and destruction box. Finally, progress has recently been made in the application of antisense technology in order to target CDK activity.

The interactions of flavonoids within neuronal signalling pathways

“…Flavonoid-induced activation of ERK1/2 or PI3K/Akt pathways acts to stimulate neuronal survival and/or enhance synaptic plasticity and long-term potentiation relevant to the laying down of memory. In addition, inhibitory actions within JNK and p38 pathways are likely to be neuroprotective in the presence of stress [56,73,154]. This inhibition is mediated via the binding of the polyphenols to the ATP binding site, presumably causing three-dimensional structural changes in the kinase leading to its inactivity.…”

Targeting the cell cycle for cancer therapy

“…Small molecules that interact specifically with the ATP-binding site of CDKs represent the most immediate opportunity to allow pharmacological design. A group of compounds that occupy the ATP-binding pocket of the enzyme and are competitive with the ATP have been characterized Mani et al, 2000;Fischer and Lane, 2000;Senderowicz and Sausville, 2000). Chemical CDK inhibitors can be subdivided into the following eight families: purine derivatives (including 6-DMAP, olomucine, roscovitine and purvanolol), butyrolactone I, flavopiridols, staurosporine and derivatives, toyocamycin, 9-hydroxyellypticine, polysulphates (including suramin) and paullones, although new ones are constantly being discovered.…”

β-Escin inhibits colonic aberrant crypt foci formation in rats and regulates the cell cycle growth by inducing p21waf1/cip1 in colon cancer cells

“…22,23). In addition, cdk inhibitors are thought to be good target molecules for the development of anticancer agents that can selectively control the cell cycle in cancer cells (24,25). In the present study, we have assessed the potential chemopreventive efficacy of h-escin on azoxymethane-induced rat colon cancer model using ACF as efficacy marker in male F344 rats.…”