Switching Reversibility to Irreversibility in Glycogen Synthase Kinase 3 Inhibitors: Clues for Specific Design of New Compounds

Perez, Daniel I.; Palomo, Valle; Perez, Concepcion; Gil, Carmen; Dans, Pablo D.; Javier Luque, F.; Conde, Santiago; Martinez, Ana

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 IC50 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.

Más información

Título según WOS: ID WOS:000291709100005 Not found in local WOS DB
Título de la Revista: JOURNAL OF MEDICINAL CHEMISTRY
Volumen: 54
Número: 12
Editorial: AMER CHEMICAL SOC
Fecha de publicación: 2011
Página de inicio: 4042
Página final: 4056
DOI:

10.1021/jm1016279

Notas: ISI