期刊
CHEMBIOCHEM
卷 23, 期 4, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.202100603
关键词
cross coupling; inhibitors; protein-protein interactions; SH2 domains; transcription factors
资金
- Deutsche Forschungsgemeinschaft [BE 4572/4-2]
Stafia-1 is presented as a compound that selectively inhibits the transcription factor STAT5a, while being selective over STAT5b. Researchers have outlined a synthetic strategy for asymmetrically substituted m-terphenyl phosphates to address the asymmetric STAT5a binding site more specifically. The synthetic methodology and activity analysis provide insights into the structure-activity relationships of m-terphenyl phosphates as selective STAT5a inhibitors.
We recently presented Stafia-1 as the first chemical entity that inhibits the transcription factor STAT5a with selectivity over the highly homologous STAT5b. Stafia-1, which was identified from a series of symmetrically substituted m-terphenyl phosphates, binds to the interface between the SH2 domain and the linker domain of STAT5a. Here, we outline a synthetic strategy for the synthesis of asymmetrically substituted m-terphenyl phosphates, which can be tailored to address their asymmetric STAT5a binding site in a more specific manner. The asymmetrically substituted m-terphenyl phosphate with the highest activity against STAT5a was converted to a phosphatase-stable monofluoromethylene phosphonate. The synthetic methodology and activity analysis described here provide first insights into the structure-activity relationships of m-terphenyl phosphates for use as selective STAT5a inhibitors.
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