Thienylhalomethylketones: Irreversible glycogen synthase kinase 3 inhibitors as useful pharmacological tools.
Thienylhalomethylketones, whose chemical, biological, and pharmaceutical data are here reported, are the first irreversible inhibitors of GSK-3beta described to date. Their inhibitory activity is likely related to the cysteine residue present in the ATP-binding site, which is proposed as a relevant residue for modulation of GSK-3 activity. The good cell permeability of the compounds allows them to be used in different cell models. Overall, the results presented here support the potential use of halomethylketones as pharmacological tools for the study of GSK-3beta functions and suggest a new mechanism for GSK-3beta inhibition that may be considered for further drug design.
Perez
Daniel I
DI
Instituto de Química Médica-CSIC, Juan de la Cierva 3, 28006 Madrid, Spain.
Conde
Santiago
S
Pérez
Concepción
C
Gil
Carmen
C
Simon
Diana
D
Wandosell
Francisco
F
Moreno
Francisco J
FJ
Gelpí
José L
JL
Luque
Francisco J
FJ
Martínez
Ana
A
D000818:Animals; D001665:Binding Sites; D002463:Cell Membrane Permeability; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D007659:Ketones; D047428:Protein Kinase Inhibitors; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3