Exploiting structural principles to design cyclin-dependent kinase inhibitors.
Although cyclin-dependent kinases (CDKs) have been extensively targeted in anti cancer drug design, no CDK inhibitor has yet been approved for use in cancer therapy. While this may in part be because inhibitors clinically evaluated to date have not demonstrated clean inhibition of a single CDK, another contributing factor is an apparent latent functional redundancy in the CDK cell-cycle regulatory system. This further complicates the already challenging goal of targeting CDKs, since it implies that a therapeutically useful inhibitor will have to selectively inhibit more than one CDK family member among the complement of cellular proteins. Despite these difficulties, achieving an appropriate profile of CDK inhibition may yet be possible using ATP-competitive inhibitors, thanks to advances in computational and experimental methods of drug design. However, as an alternative to ATP-competitive inhibitors, inhibitors that interfere with a CDK-specific protein:protein interaction, such as that which occurs at the recruitment site found on several cyclins, may offer a route to a therapeutically useful inhibitory profile.
Noble
Martin
M
Laboratory of Molecular Biophysics and Department of Biochemistry, The Rex Richards Building, South Parks Road, Oxford, OX1 3QU, UK. martin.noble@biop.ox.ac.uk
Barrett
Paul
P
Endicott
Jane
J
Johnson
Louise
L
McDonnell
Jim
J
Robertson
Giles
G
Zawaira
Alex
A
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D025941:Protein Interaction Mapping; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D018844:Cyclin-Dependent Kinases