Small molecule substrate phosphorylation site inhibitors of protein kinases: approaches and challenges
- PMID: 25494294
- PMCID: PMC4301090
- DOI: 10.1021/cb5008376
Small molecule substrate phosphorylation site inhibitors of protein kinases: approaches and challenges
Abstract
Protein kinases are important mediators of cellular communication and attractive drug targets for many diseases. Although success has been achieved with developing ATP-competitive kinase inhibitors, the disadvantages of ATP-competitive inhibitors have led to increased interest in targeting sites outside of the ATP binding pocket. Kinase inhibitors with substrate-competitive, ATP-noncompetitive binding modes are promising due to the possibility of increased selectivity and better agreement between biochemical and in vitro potency. However, the difficulty of identifying these types of inhibitors has resulted in significantly fewer small molecule substrate phosphorylation site inhibitors being reported compared to ATP-competitive inhibitors. This review surveys reported substrate phosphorylation site inhibitors and methods that can be applied to the discovery of such inhibitors, including a discussion of the challenges inherent to these screening methods.
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References
-
- Manning G.; Whyte D. B.; Martinez R.; Hunter T.; Sudarsanam S. (2002) The Protein Kinase Complement of the Human Genome. Science 298, 1912–1934. - PubMed
-
- Johnson S. A.; Hunter T. (2005) Kinomics: methods for deciphering the kinome. Nat. Methods 2, 17–25. - PubMed
-
- Ryšlavá H.; Doubnerová V.; Kavan D.; Vaněk O. (2013) Effect of posttranslational modifications on enzyme function and assembly. J. Proteomics 92, 80–109. - PubMed
-
- Pawson T.; Scott J. D. (2005) Protein phosphorylation in signaling – 50 years and counting. Trends Biochem. Sci. 30, 286–290. - PubMed
-
- Graves J. D.; Krebs E. G. (1999) Protein Phosphorylation and Signal Transduction. Pharmacol. Ther. 82, 111–121. - PubMed
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