Bioorganic & Medicinal Chemistry 2009-01-01

Thienylhalomethylketones: Irreversible glycogen synthase kinase 3 inhibitors as useful pharmacological tools

Daniel I. Perez, Santiago Conde, Concepción Pérez, Carmen Gil, Diana Simon, Francisco Wandosell, Francisco J. Moreno, José L. Gelpí, Francisco J. Luque, Ana Martínez

Index: Bioorg. Med. Chem. 17 , 6914-25, (2009)

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Abstract

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.