title: Switching reversibility to irreversibility in glycogen synthase kinase 3 inhibitors: clues for specific design of new compounds.
abstract: Development of kinase-targeted therapies for central nervous system (CNS) diseases is a great challenge. Glycogen synthase kinase 3 (GSK-3) offers a great potential for severe CNS unmet diseases, being one of the inhibitors on clinical trials for different tauopathies. Following our hypothesis based on the enhanced reactivity of residue Cys199 in the binding site of GSK-3, we examine here the suitability of phenylhalomethylketones as irreversible inhibitors. Our data confirm that the halomethylketone unit is essential for the inhibitory activity. Moreover, addition of the halomethylketone moiety to reversible inhibitors turned them into irreversible inhibitors with IC(50) values in the nanomolar range. Overall, the results point out that these compounds might be useful pharmacological tools to explore physiological and pathological processes related to signaling pathways regulated by GSK-3 opening new avenues for the discovery of novel GSK-3 inhibitors.
authors.affiliation: Instituto de Química Medica-CSIC, Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Perez
authors.forename: Valle
authors.initials: V
authors.lastname: Palomo
authors.forename: Concepción
authors.initials: C
authors.lastname: Pérez
authors.forename: Carmen
authors.initials: C
authors.lastname: Gil
authors.forename: Pablo D
authors.initials: PD
authors.lastname: Dans
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Luque
authors.forename: Santiago
authors.initials: S
authors.lastname: Conde
authors.forename: Ana
authors.initials: A
authors.lastname: Martínez
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D002491:Central Nervous System Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002531:Cerebellum / Q000166:cytology; D015195:Drug Design; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006801:Humans; D066298:In Vitro Techniques; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D051381:Rats; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D016875:tau Proteins / Q000378:metabolism
chemical_list: D002491:Central Nervous System Agents; D007659:Ketones; D017981:Receptors, Neurotransmitter; D016875:tau Proteins; D000255:Adenosine Triphosphate; D038362:Glycogen Synthase Kinase 3