Discovery of protein phosphatase inhibitor classes by biology-oriented synthesis

doi:10.1073/pnas.0601490103

Discovery of protein phosphatase inhibitor classes by biology-oriented synthesis

*Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, D-44227 Dortmund, Germany;
^†Fachbereich 3, Chemische Biologie, Universität Dortmund, Otto-Hahn-Strasse 6, D-44227 Dortmund, Germany;
^‡Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Johann Wolfgang Goethe-Universität, Marie-Curie-Strasse 11, D-60439 Frankfurt am Main, Germany;
^§Max Planck Institute for Molecular Biomedicine, Von-Esmarch-Strasse 56, D-48149 Münster, Germany; and
^¶AnalytiCon Discovery, Hermannswerder Haus 17, D-14473 Potsdam, Germany

Edited by Jerrold Meinwald, Cornell University, Ithaca, NY, and approved May 15, 2006 (received for review February 22, 2006)

Abstract

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.

Footnotes

^‖To whom correspondence on compound identity, purity, and supply should be addressed. E-mail: o.schwarz{at}ac-discovery.com
**To whom correspondence should be addressed. E-mail: herbert.waldmann{at}mpi-dortmund.mpg.de
Author contributions: H.W. designed research; A.N.-M., I.R.-C., H.P., C.R., S.S., and O.S. performed research; K.S., H.J.S., D.V., G.C., S.S., O.S., and H.S. contributed new reagents/analytic tools; A.N.-M., I.R.-C., H.P., and H.W. analyzed data; and H.W. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

Abbreviation:

BIOS,

biology-oriented synthesis;

HMBA,

4-(hydroxymethyl)benzoic acid amide;

NP,

natural product;

SAR,

structure–activity relationship;

SCONP,

structural classification of natural products;

TFA,

trifluoroacetic acid;

TMSCl,

trimethylsilylchloride.