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|3tc5, resolution 1.40Å ()|
|Gene:||PIN1 (Homo sapiens)|
|Related:||1pin, 2zr6, 2itk, 2q5a|
Selective targeting of disease-relevant protein binding domains by O-phosphorylated natural product derivatives
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.
Selective Targeting of Disease-Relevant Protein Binding Domains by O-Phosphorylated Natural Product Derivatives., Graber M, Janczyk W, Sperl B, Elumalai N, Kozany C, Hausch F, Holak TA, Berg T, ACS Chem Biol. 2011 Aug 10. PMID:21797253
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.