Tampering with Cell Division by Using Small‐Molecule Inhibitors of CDK–CKS Protein Interactions |
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| Authors: | Dr Amel Hamdi Aurélien Lesnard Peggy Suzanne Thomas Robert Dr Maria A Miteva Morgan Pellerano Dr Bruno Didier Dr Elizabeth Ficko‐Blean Prof Annelise Lobstein Prof Marcel Hibert Prof Sylvain Rault Dr May C Morris Dr Pierre Colas |
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| Affiliation: | 1. UMSR 3151 CNRS, Université Pierre et Marie Curie, Protein Phosphorylation and Human Disease Unit, P2I2group, Station Biologique, Place Georges Teissier, 29680 Roscoff (France);2. UNICAEN, CERMN, Centre d'Etudes et de Recherche sur le Médicament de Normandie, FR CNRS INC3M, SF ICORE, Université de Caen Basse‐Normandie, UFR des Sciences Pharmaceutiques, Boulevard Becquere–CS 14032–14032, Caen Cedex 5 (France);3. MTi, Université Paris Diderot, INSERM UMR‐S 973, Bat. Lamarck, 5e étage, 5 rue Marie‐Andrée Lagroua Weill‐Halle, 75205 Paris Cedex 13 (France);4. Institut des Biomolécules Max Mousseron, IBMM‐CNRS‐UMR 5247, Faculté de Pharmacie, Université de Montpellier, 15, avenue Charles Flahault, 34093 Montpellier Cedex 5 (France);5. Laboratoire d'Innovation Thérapeutique, UMR 7200 CNRS, Université de Strasbourg, Faculté de Pharmacie, 74, route du Rhin, 67400 Illkirch (France);6. UMR8227 CNRS, Université Pierre et Marie Curie, Station Biologique, Place Georges Teissier, 29680 Roscoff (France) |
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| Abstract: | Cyclin‐dependent kinases (CDKs) control many cellular processes and are considered important therapeutic targets. Large collections of inhibitors targeting CDK active sites have been discovered, but their use in chemical biology or drug development has been often hampered by their general lack of specificity. An alternative approach to develop more specific inhibitors is targeting protein interactions involving CDKs. CKS proteins interact with some CDKs and play important roles in cell division. We discovered two small‐molecule inhibitors of CDK–CKS interactions. They bind to CDK2, do not inhibit its enzymatic activity, inhibit the proliferation of tumor cell lines, induce an increase in G1 and/or S‐phase cell populations, and cause a decrease in CDK2, cyclin A, and p27Kip1 levels. These molecules should help decipher the complex contributions of CDK–CKS complexes in the regulation of cell division, and they might present an interesting therapeutic potential. |
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| Keywords: | cytostatic agents natural products protein kinases protein– protein interactions |
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