Discovery of protein phosphatase inhibitor classes by biology-oriented synthesis.
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.
Nören-Müller
Andrea
A
Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, D-44227 Dortmund, Germany.
Reis-Corrêa
Ivan
I
Prinz
Heino
H
Rosenbaum
Claudia
C
Saxena
Krishna
K
Schwalbe
Harald J
HJ
Vestweber
Dietmar
D
Cagna
Guiseppe
G
Schunk
Stefan
S
Schwarz
Oliver
O
Schiewe
Hajo
H
Waldmann
Herbert
H
D001688:Biological Products / Q000138:chemical synthesis* / Q000737:chemistry / Q000145:classification*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000145:classification*; D006801:Humans; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry*
D001688:Biological Products; D004791:Enzyme Inhibitors; D010749:Phosphoprotein Phosphatases