Design of a novel class of peptide inhibitors of cyclin-dependent kinase/cyclin activation.
Cyclin dependent kinases (CDKs) are key regulators of the cell cycle progression and therefore constitute excellent targets for the design of anticancer agents. Most of the inhibitors identified to date inhibit kinase activity by interfering with the ATP-binding site of CDKs. We recently proposed that the protein/protein interface and conformational changes required in the molecular mechanism of CDK2-cyclin A activation were potential targets for the design of specific inhibitors of cell cycle progression. To this aim, we have designed and characterized a small peptide, termed C4, derived from amino acids 285-306 in the alpha5 helix of cyclin A. We demonstrate that this peptide does not interfere with complex formation but forms stable complexes with CDK2-cyclin A. The C4 peptide significantly inhibits kinase activity of complexes harboring CDK2 in a competitive fashion with respect to substrates but does not behave as an ATP antagonist. Moreover, when coupled with the protein transduction domain of Tat, the C4 peptide blocks the proliferation of tumor cell lines, thereby constituting a potent lead for the development of specific CDK-cyclin inhibitors.
Gondeau
Claire
C
Centre de Recherches de Biochimie Macromoléculaire, Department of Molecular Biophysics and Therapeutics, FRE-2593 CNRS, 1919 Route de Mende, 34293 Montpellier, France.
Gerbal-Chaloin
Sabine
S
Bello
Paul
P
Aldrian-Herrada
Gudrun
G
Morris
May C
MC
Divita
Gilles
G
D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D019925:Cyclin A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2; D015195:Drug Design; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism*; D015696:Gene Products, tat / Q000235:genetics / Q000378:metabolism; D006801:Humans; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment
D000970:Antineoplastic Agents; D019925:Cyclin A; D004791:Enzyme Inhibitors; D015696:Gene Products, tat; D046911:Macromolecular Substances; D010455:Peptides; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2