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Here, we report <jats:italic>p<\/jats:italic>\u2010biaryl phosphates and phosphonates as the first small\u2010molecule inhibitors of STAT4. The most potent <jats:italic>p<\/jats:italic>\u2010biaryl phosphate inhibited the protein\u2013protein interaction domain of STAT4, the SH2 domain, with submicromolar potency (<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>\u00a0=\u00a00.35\u00a0\u00b5M) and 14\u2010fold selectivity over the closely related family member STAT3, which has the same core peptide binding motif as STAT4. Further development resulted in the phosphatase\u2010stable inhibitor Stafori\u20101, which protected STAT4 but not STAT3, against thermal denaturation in cell lysates. Its cell\u2010permeable prodrug Pomstafori\u20101 selectively inhibited STAT4 phosphorylation in cultured human cells at low micromolar concentrations. Our data open up the possibility of exploring STAT4 as a target protein for small molecules in the treatment of unmet medical needs.<\/jats:p>","DOI":"10.1002\/anie.202504420","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T16:40:21Z","timestamp":1741711221000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Biaryl Phosphates and Phosphonates as Selective Inhibitors of the Transcription Factor STAT4"],"prefix":"10.1002","volume":"64","author":[{"given":"Nadiya","family":"Brovchenko","sequence":"first","affiliation":[{"name":"Institute of Organic Chemistry Leipzig University  Johannisallee 29 04103 Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Berg","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry Leipzig University  Johannisallee 29 04103 Leipzig 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