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Selective targeting of disease-relevant protein binding domains by O-phosphorylated natural product derivatives.

ACS chemical biology (2011-07-30)
Martin Gräber, Weronika Janczyk, Bianca Sperl, Nagarajan Elumalai, Christian Kozany, Felix Hausch, Tad A Holak, Thorsten Berg
ABSTRACT

Phosphorylation-dependent protein binding domains are crucially important for intracellular signaling pathways and thus highly relevant targets in chemical biology. By screening of chemical libraries against 12 structurally diverse phosphorylation-dependent protein binding domains, we have identified fosfosal and dexamethasone-21-phosphate as selective inhibitors of two antitumor targets: the SH2 domain of the transcription factor STAT5b and the substrate-binding domain of the peptidyl-prolyl isomerase Pin1, respectively. Both compounds are phosphate prodrugs with documented clinical use as anti-inflammatory agents in humans and were discovered with a high hit rate from a small subgroup within the screening library. Our study indicates O-phosphorylation of appropriately preselected natural products or natural product derivatives as a generally applicable strategy for the identification of non-reactive and non-peptidic ligands of phosphorylation-dependent protein binding domains. Moreover, our data indicate that it would be advisable to monitor the bioactivities of clinically used prodrugs in their uncleaved state against phosphorylation-dependent protein binding domains.

MATERIALS
Product Number
Brand
Product Description

Dexamethasone sodium phosphate, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Dexamethasone 21-phosphate disodium salt, ≥98%