Reversible Covalent Inhibition of a Protein Target

Electron‐deficient Michael acceptors can be used in reversible addition/elimination reactions with thiols. These electrophiles were used to convert a known irreversible kinase inhibitor into a covalent and reversible inhibitor. Such an approach might provide high‐affinity binders with increased sele...

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Veröffentlicht in:	Angewandte Chemie International Edition 2012-08, Vol.51 (35), p.8699-8700
Hauptverfasser:	Lee, Chang-Uk, Grossmann, Tom N.
Format:	Artikel
Sprache:	eng
Schlagworte:	Binders Binding Sites Covalence Crystallography, X-Ray cysteine Cysteine - chemistry Drug Design Inhibition Inhibitors Kinases Michael addition Protein Kinase Inhibitors - chemistry Protein Kinases - chemistry Protein Kinases - metabolism Protein Structure, Tertiary Proteins reversibility Ribosomal Protein S6 Kinases, 90-kDa - chemistry Ribosomal Protein S6 Kinases, 90-kDa - metabolism Risk Selectivity Thiols
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Beschreibung
Zusammenfassung:	Electron‐deficient Michael acceptors can be used in reversible addition/elimination reactions with thiols. These electrophiles were used to convert a known irreversible kinase inhibitor into a covalent and reversible inhibitor. Such an approach might provide high‐affinity binders with increased selectivity without the toxicological risks associated with irreversible protein modifications.
ISSN:	1433-7851 1521-3773
DOI:	10.1002/anie.201203341