Details

Autor(en) / Beteiligte

• Poot, Alex J
• van Ameijde, Jeroen
• Slijper, Monique
• van den Berg, Adriënne
• Hilhorst, Riet
• Ruijtenbeek, Rob
• Rijkers, Dirk T.S
• Liskamp, Rob M.J

Titel

Development of Selective Bisubstrate-Based Inhibitors Against Protein Kinase C (PKC) Isozymes By Using Dynamic Peptide Microarrays

Ist Teil von

• Chembiochem : a European journal of chemical biology, 2009-08, Vol.10 (12), p.2042-2051

Ort / Verlag

Weinheim: Wiley-VCH Verlag

Erscheinungsjahr

2009

Quelle

MEDLINE

Beschreibungen/Notizen

• Kinase inhibitors are increasingly important in drug development. Because the majority of current inhibitors target the conserved ATP-binding site, selectivity might become an important issue. This could be particularly problematic for the potential drug target protein kinase C (PKC), of which twelve isoforms with high homology exist in humans. A strategy to increase selectivity is to prepare bisubstrate-based inhibitors that target the more selective peptide-binding site in addition to the ATP-binding site. In this paper a generally applicable, rapid methodology is presented to discover such bisubstrate-based leads. Dynamic peptide microarrays were used to find peptide-binding site inhibitors. These were linked with chemoselective click chemistry to an ATP-binding site inhibitor, and this led to novel bisubstrate structures. The peptide microarrays were used to evaluate the resulting inhibitors. Thus, novel bisubstrate-based inhibitors were obtained that were both more potent and selective compared to their constituent parts. The most promising inhibitor has nanomolar affinity and selectivity towards PKCθ amongst three isozymes.