Document Detail


Selective Detection of Allosteric Phosphatase Inhibitors.
MedLine Citation:
PMID:  23611635     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Normal cellular function, such as signal transduction, is largely controlled by the reversible phosphorylation of cellular proteins catalyzed by two major classes of enzymes, kinases and phosphatases. A misbalance in this complex and dynamic interplay leads to a variety of severe diseases, such as cancer, inflammation or autoimmune diseases. This makes kinases as well as phosphatases equally attractive targets for therapeutic manipulation by small molecules. While the development of kinase inhibitors has resulted in several blockbuster drugs, such as imatinib, with remarkable success in the clinic and sales of many billions of U.S. dollars per year, not a single phosphatase inhibitor has yet been approved for clinical use. Similar to the kinase world, substrate-competitive phosphatase inhibitors have been developed, but were not suitable for further development into clinical candidates due to their charge and limited selec-tivity. Research efforts, therefore, have shifted to the exploi-tation of allosteric sites that can regulate phosphatase activi-ty and may enable the discovery of novel modulators of phosphatase activity with much improved pharmacological properties. However, assay systems, which enable the straightforward discovery of these inhibitor types, are miss-ing. Here, we present a novel binding assay capable of detect-ing ligands of an allosteric pocket of the protein tyrosine phosphatase 1B (PTP1B). This assay is suitable for high throughput screening (HTS) and selectively detects ligands which bind to this unique site with a clear discrimination from substrate-competitive ligands.
Authors:
Ralf Schneider; Claudia Beumer; Jeffrey R Simard; Christian Grütter; Daniel Rauh
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-4-23
Journal Detail:
Title:  Journal of the American Chemical Society     Volume:  -     ISSN:  1520-5126     ISO Abbreviation:  J. Am. Chem. Soc.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-4-24     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7503056     Medline TA:  J Am Chem Soc     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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