Aloisines, a new family of CDK/GSK-3 inhibitors. SAR study, crystal structure in complex with CDK2, enzyme selectivity, and cellular effects
Résumé
Cyclin-dependent kinases (CDKs) regulate the cell cycle, apoptosis, neuronal functions, transcription, and exocytosis. The observation of CDK deregulations in various pathological situations suggests that CDK inhibitors may have a therapeutic value. In this article, we report on the identification of 6-phenyl[5H]pyrrolo[2,3-b]pyrazines (aloisines) as a novel potent CDK inhibitory scaffold. A selectivity study performed on 26 kinases shows that aloisine A is highly selective for CDK1/cyclin B, CDK2/cyclin A-E, CDK5/p25, and GSK-3 alpha/beta; the two latter enzymes have been implicated in Alzheimer's disease. Kinetic studies, as well as the resolution of a CDK2-aloisine cocrystal structure, demonstrate that aloisines act by competitive inhibition of ATP binding to the catalytic subunit of the kinase. As observed with all inhibitors reported so far, aloisine interacts with the ATP-binding pocket through two hydrogen bonds with backbone nitrogen and oxygen atoms of Leu 83. Aloisine inhibits cell proliferation by arresting cells in both G1 and G2.
Mots clés
- Adenosine Triphosphate/chemistry Antineoplastic Agents/*chemical synthesis/chemistry/pharmacology Binding
- Competitive CDC2 Protein Kinase/antagonists & inhibitors *CDC2-CDC28 Kinases Cell Division/drug effects Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinase 5 Cyclin-Dependent Kinases/*antagonists & inhibitors/chemistry Enzyme Inhibitors/*chemical synthesis/chemistry/pharmacology Glycogen Synthase Kinase 3/*antagonists & inhibitors/chemistry Humans Hydrogen Bonding Models
- Molecular Molecular Conformation Neurons/cytology/drug effects Protein-Serine-Threonine Kinases/*antagonists & inhibitors/chemistry Pyrazines/*chemical synthesis/chemistry/pharmacology Research Support
- Non-U.S. Gov't Structure-Activity Relationship Tumor Cells
- Cultured