Scientific Article
previous document  unige:24691  next document
add to browser collection
Title

Cysteine Mapping in Conformationally Distinct Kinase Nucleotide Binding Sites: Application to the Design of Selective Covalent Inhibitors

Authors
Leproult, Emeline
Barluenga, Sofia
Moras, Dino
Wurtz, Jean-Marie
Published in Journal of Medicinal Chemistry. 2011, vol. 54, no. 5, p. 1347-1355
Abstract Kinases have emerged as one of the most prolific therapeutic targets. An important criterion in the therapeutic success of inhibitors targeting the nucleotide binding pocket of kinases is the inhibitor residence time. Recently, covalent kinase inhibitors have attracted attention since they confer terminal inhibition and should thus be more effective than reversible inhibitors with transient inhibition. The most robust approach to design irreversible inhibitors is to capitalize on the nucleophilicity of a cysteine thiol group present in the target protein. Herein, we report a systematic analysis of cysteine residues present in the nucleotide binding site of kinases, which could be harnessed for irreversible inhibition, taking into consideration the different kinase conformations. We demonstrate the predictive power of this analysis with the design and validation of an irreversible inhibitor of KIT/PDGFR kinases. This is the first example of a covalent kinase inhibitor that combines a pharmacophore addressing the DFG-out conformation with a covalent trap.
Identifiers
Full text
Article (Published version) (4.6 MB) - document accessible for UNIGE members only Limited access to UNIGE
Other version: http://pubs.acs.org/doi/abs/10.1021/jm101396q
Citation
(ISO format)
LEPROULT, Emeline et al. Cysteine Mapping in Conformationally Distinct Kinase Nucleotide Binding Sites: Application to the Design of Selective Covalent Inhibitors. In: Journal of Medicinal Chemistry, 2011, vol. 54, n° 5, p. 1347-1355. https://archive-ouverte.unige.ch/unige:24691

158 hits

2 downloads

Update

Deposited on : 2012-12-18

Export document
Format :
Citation style :