title: Selective targeting of disease-relevant protein binding domains by O-phosphorylated natural product derivatives.
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.
authors.forename: Martin
authors.initials: M
authors.lastname: Gräber
authors.forename: Weronika
authors.initials: W
authors.lastname: Janczyk
authors.forename: Bianca
authors.initials: B
authors.lastname: Sperl
authors.forename: Nagarajan
authors.initials: N
authors.lastname: Elumalai
authors.forename: Christian
authors.initials: C
authors.lastname: Kozany
authors.forename: Felix
authors.initials: F
authors.lastname: Hausch
authors.forename: Tad A
authors.initials: TA
authors.lastname: Holak
authors.forename: Thorsten
authors.initials: T
authors.lastname: Berg
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D003907:Dexamethasone / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D010755:Organophosphates / Q000494:pharmacology*; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018909:src Homology Domains
chemical_list: D000970:Antineoplastic Agents; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D010755:Organophosphates; D050799:STAT5 Transcription Factor; C000380:fosfosal; C004180:dexamethasone 21-phosphate; D003907:Dexamethasone; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase