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Journal/Book: Proceedings of the National Academy of Sciences
Published: 2006
Pages: 10606 - 10611
Volume: 103
Issue: 28
Accession no.: 122

Discovery of protein phosphatase inhibitor classes by biology-oriented synthesis

Andrea Nören-Müller, Reis-Corrêa, Ivan, Heino Prinz, Rosenbaum, Claudia, Krishna Saxena, Schwalbe, Harald J., Vestweber, Dietmar, Cagna, Guiseppe, Schunk, Stefan, Schwarz, Oliver, Schiewe, Hajo, Herbert Waldmann
Protein phosphatases have very recently emerged as important targets for chemical biology and medicinal chemistry research, and new phosphatase inhibitor classes are in high demand. The underlying frameworks of natural products represent the evolutionarily selected fractions of chemical space explored by nature so far and meet the criteria of relevance to nature and biological prevalidation most crucial to inhibitor development. We refer to synthesis efforts and compound collection development based on these criteria as biology-oriented synthesis. For the discovery of phosphatase inhibitor classes by means of this approach, four natural product-derived or -inspired medium-sized compound collections were synthesized and investigated for inhibition of the tyrosine phosphatases VE-PTP, Shp-2, PTP1B, MptpA, and MptpB and the dual-specificity phosphatases Cdc25A and VHR. The screen yielded four unprecedented and selective phosphatase inhibitor classes for four phosphatases with high hit rates. For VE-PTP and MptpB the first inhibitors were discovered. These results demonstrate that biology-oriented synthesis is an efficient approach to the discovery of new compound classes for medicinal chemistry and chemical biology research that opens up new opportunities for the study of phosphatases, which may lead to the development of new drug candidates.
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Prof. Dr. Harald Schwalbe
Institut für Organische Chemie und Chemische Biologie
Johann Wolfgang Goethe Universität
Max-von-Laue-Str. 7
D-60438 Frankfurt am Main
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