Asymmetrically Substituted m-Terphenyl Phosphates Inhibit the Transcription Factor STAT5a

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.

Automated summary

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.