Biaryl Phosphate-Based Inhibitors of the Transcription Factor STAT4.

The transcription factor signal transducer and activator of transcription (STAT)4 is a potential target for autoimmune diseases, such as inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and diabetes mellitus. p-Biphenyl phosphate is reported as an inhibitor of the STAT4 Src homology 2 domain, and it is developed to the phosphonate-based inhibitor Stafori-1. Herein, structure-activity relationships of p-biaryl phosphates against STAT4 and their selectivity profiles against other STAT proteins are reported. The most potent biaryl phosphate-based inhibitor originating from this article, Stafori-2, contains the same aryl moieties as the phosphonate Stafori-1. However, Stafori-2 is more potent than Stafori-1 in fluorescence polarization assays and by isothermal titration calorimetry.