# Biaryl Phosphate‐Based Inhibitors of the Transcription Factor STAT4

## TL;DR

Researchers developed a new biaryl phosphate compound, Stafori-2, which is more effective at inhibiting the STAT4 protein than previous versions, potentially offering better treatment for autoimmune diseases.

## Contribution

The study introduces Stafori-2, a more potent biaryl phosphate inhibitor of STAT4 compared to Stafori-1, with improved structure-activity relationships and selectivity.

## Key findings

- Stafori-2 is more potent than Stafori-1 in inhibiting STAT4.
- Structure-activity relationships and selectivity profiles of p-biaryl phosphates against STAT4 are reported.
- Stafori-2 shows improved performance in fluorescence polarization and isothermal titration calorimetry assays.

## Abstract

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.

The transcription factor signal transducer and activator of transcription (STAT)4 is a potential target for autoimmune diseases. p‐Biphenyl phosphate is reported as an inhibitor of the STAT4 Src homology 2 domain and it is developed to the phosphonate Stafori‐1. Here, structure–activity relationships and selectivity profiles of p‐biaryl phosphates are presented. The most potent p‐biaryl phosphate inhibitor Stafori‐2 is more potent against STAT4 than Stafori‐1.© 2025 WILEY‐VCH GmbH