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
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