title: Potent inhibitors of CDK5 derived from roscovitine: synthesis, biological evaluation and molecular modelling.
abstract: Cyclin dependent kinase 5 (CDK5) is a serine/threonine kinase belonging to the cyclin dependent kinase (CDK) family. CDK5 is involved in numerous neuronal diseases (including Alzheimer's or Parkinson's diseases, stroke, traumatic brain injury), pain signaling and cell migration. In the present Letter, we describe syntheses and biological evaluations of new 2,6,9-trisubstituted purines, structurally related to roscovitine, a promising CDK inhibitor currently in clinical trials (CDK1/Cyclin B, IC(50)=350 nM; CDK5/p25, IC(50)=200 nM). These new molecules were synthesized using an original Buchwald-Hartwig catalytic procedure; several compounds (3j, 3k, 3l, 3e, 4k, 6b, 6c) displayed potent kinase inhibitory potencies against CDK5 (IC(50) values ranging from 17 to 50 nM) and showed significant cell death inducing activities (IC(50) values ranging from 2 to 9 μM on SH-SY5Y). The docking of the inhibitors into the ATP binding domain of the CDK5 catalytic site highlighted the discriminatory effect of a hydrogen bond involving the CDK5 Lys-89. In addition, the calculated final energy balances for complexation measured for several inhibitors is consistent with the ranking of the IC(50) values. Lastly, we observed that several compounds exhibit submicromolar activities against DYRK1A (dual specificity, tyrosine phosphorylation regulated kinase 1A), a kinase involved in Down syndrome and Alzheimer's disease (3g, 3h, 4m; IC(50) values ranging from 300 to 400 nM).
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270 Paris cedex 06, France. luc.demange@parisdescartes.fr
authors.forename: Luc
authors.initials: L
authors.lastname: Demange
authors.forename: Fatma Nait
authors.initials: FN
authors.lastname: Abdellah
authors.forename: Olivier
authors.initials: O
authors.lastname: Lozach
authors.forename: Yoan
authors.initials: Y
authors.lastname: Ferandin
authors.forename: Nohad
authors.initials: N
authors.lastname: Gresh
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.forename: Hervé
authors.initials: H
authors.lastname: Galons
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D000077546:Roscovitine; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; D051360:Cyclin-Dependent Kinase 5