title: Recent advances in designing substrate-competitive protein kinase inhibitors.
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 substrate-competitive 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.
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea.
authors.forename: Ki-Cheol
authors.initials: KC
authors.lastname: Han
authors.forename: So Yeon
authors.initials: SY
authors.lastname: Kim
authors.forename: Eun Gyeong
authors.initials: EG
authors.lastname: Yang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D019295:Computational Biology / Q000379:methods; D016503:Drug Delivery Systems; D015195:Drug Design; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction; D013379:Substrate Specificity
chemical_list: D010455:Peptides; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D011494:Protein Kinases