Abstract
Protein kinases play central roles in cellular signaling pathways and their abnormal phosphorylation activity is inseparably linked with various human diseases. Therefore, modulation of kinase activity using potent inhibitors is an attractive strategy for the treatment of human disease. While most protein kinase inhibitors in clinical development are mainly targeted to the highly conserved ATP-binding sites and thus likely promiscuously inhibit multiple kinases including kinases unrelated to diseases, protein substratecompetitive inhibitors are more selective and expected to be promising therapeutic agents. Most substrate-competitive inhibitors mimic peptides derived from substrate proteins, or from inhibitory domains within kinases or inhibitor proteins. In addition, bisubstrate inhibitors are generated by conjugating substrate-competitive peptide inhibitors to ATP-competitive inhibitors to improve affinity and selectivity. Although structural information on protein kinases provides invaluable guidance in designing substrate-competitive inhibitors, other strategies including bioinformatics, computational modeling, and high-throughput screening are often employed for developing specific substrate-competitive kinase inhibitors. This review focuses on recent advances in the design and discovery of substrate-competitive inhibitors of protein kinases.
Keywords: Protein kinase, inhibitor, substrate-competitive, peptide, bisubstrate, phosphorylation, ATP-binding sites, GSK-3, Src, proteases
Current Pharmaceutical Design
Title:Recent Advances in Designing Substrate-Competitive Protein Kinase Inhibitors
Volume: 18 Issue: 20
Author(s): Ki-Cheol Han, So Yeon Kim and Eun Gyeong Yang
Affiliation:
Keywords: Protein kinase, inhibitor, substrate-competitive, peptide, bisubstrate, phosphorylation, ATP-binding sites, GSK-3, Src, proteases
Abstract: Protein kinases play central roles in cellular signaling pathways and their abnormal phosphorylation activity is inseparably linked with various human diseases. Therefore, modulation of kinase activity using potent inhibitors is an attractive strategy for the treatment of human disease. While most protein kinase inhibitors in clinical development are mainly targeted to the highly conserved ATP-binding sites and thus likely promiscuously inhibit multiple kinases including kinases unrelated to diseases, protein substratecompetitive inhibitors are more selective and expected to be promising therapeutic agents. Most substrate-competitive inhibitors mimic peptides derived from substrate proteins, or from inhibitory domains within kinases or inhibitor proteins. In addition, bisubstrate inhibitors are generated by conjugating substrate-competitive peptide inhibitors to ATP-competitive inhibitors to improve affinity and selectivity. Although structural information on protein kinases provides invaluable guidance in designing substrate-competitive inhibitors, other strategies including bioinformatics, computational modeling, and high-throughput screening are often employed for developing specific substrate-competitive kinase inhibitors. This review focuses on recent advances in the design and discovery of substrate-competitive inhibitors of protein kinases.
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Cite this article as:
Han Ki-Cheol, Yeon Kim So and Gyeong Yang Eun, Recent Advances in Designing Substrate-Competitive Protein Kinase Inhibitors, Current Pharmaceutical Design 2012; 18 (20) . https://dx.doi.org/10.2174/138161212800672697
DOI https://dx.doi.org/10.2174/138161212800672697 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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