Peptidomimetic Design of CDK Inhibitors Targeting theRecruitment Site of the Cyclin Subunit

Author(s): David P. Lane, Peter M. Fischer

Journal Name: Current Medicinal Chemistry - Anti-Cancer Agents
Continued as Anti-Cancer Agents in Medicinal Chemistry

Volume 3 , Issue 1 , 2003


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.

Keywords: Peptidomimetic, CDK Inhibitors, Cyclin, protein-protein interaction

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Article Details

Year: 2003
Page: [57 - 69]
Pages: 13
DOI: 10.2174/1568011033353506

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