Asymmetrically Substituted m‐Terphenyl Phosphates Inhibit the Transcription Factor STAT5a

Abstract

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.

A High-Throughput Fluorescence Polarization-Based Assay for the SH2 Domain of STAT4

“…Here, we present a detailed description of a fluorescence polarization-based assay suitable for high-throughput screening for STAT4 SH2 domain inhibitors. The assay has already proved its utility in the specificity analysis of inhibitors found to inhibit other phosphorylation-dependent protein-protein interactions [13][14][15][16][17][18].…”