Peptidomimetic design of CDK inhibitors targeting the recruitment site of the cyclin subunit.
The recognition of cyclin-dependent kinase (CDK)/cyclin complexes by various cell-cycle regulatory proteins, including certain tumour suppressors and transcription factors, occurs at least in part through a protein-protein interaction with a binding groove on the cyclin subunit. Since CDK function is generally deregulated in tumour cells, blocking of this recruitment site prevents recognition and subsequent phosphorylation of CDK substrates and offers a therapeutic approach towards restoration of checkpoint control in transformed cells. Here we discuss the finding that peptides derived from such cyclin-interacting proteins, and rendered permeable through conjugation to cellular delivery vectors, can apparently induce tumour cells to undergo apoptosis selectively. We review the current status of 3D-structural information available on cyclin-peptide interactions and we summarise our extensive peptide structure-activity relationship studies in light of this information. We also show how a combination of molecular modelling and introduction into synthetic peptides of peptidomimetic elements, such as non-natural amino acid residues and conformational constraints, is being used hopefully to arrive at drug candidates capable of modulating CDK function in a selective mechanism-based approach rather than through ATP antagonism.
McInnes
Campbell
C
Cyclacel Limited, James Lindsay Place, Dundee DD1 5JJ, Scotland, UK.
Andrews
Martin J I
MJ
Zheleva
Daniella I
DI
Lane
David P
DP
Fischer
Peter M
PM
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000737:chemistry; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D013329:Structure-Activity Relationship; D025521:Tumor Suppressor Proteins / Q000737:chemistry
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D010455:Peptides; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases