biostudies-literatureUnknownKeyes EDNational Institute of General Medical SciencesNational Science FoundationThe human protein histidine phosphatase PHPT1 is involved in several important cellular pathways and has been implicated in various cancers. However, the biological roles of this enzyme are not well understood due to a lack of chemical tools that enable its study. Herein we have identified phenylarsonic acids as general scaffolds which inhibit PHPT1 activity. Notably, phenylarsonic acids can be embedded into peptide sequences, providing the first known peptide-based inhibitors of PHPT1. In a counterscreen against a small panel of phosphatases, we demonstrate that these compounds exhibit some selectivity for PHPT1. Moreover, we show that these compounds exhibit mixed inhibition. We provide evidence that reduction of the phenylarsonic acids <i>in situ</i> by reducing agents like dithiothreitDalton transactions (Cambridge, England : 2003)https://www.ebi.ac.uk/biostudies/studies/S-EPMC12915710biostudies-literatureInhibition of PHPT1 by phenylarsonic acids.PMC12915710R35 GM1548242003513R35 GM153175Hollow SEJohnstone TCKeyes EDBarrios AMOblad PfalseInhibition of PHPT1 by phenylarsonic acids.The human protein histidine phosphatase PHPT1 is involved in several important cellular pathways and has been implicated in various cancers. However, the biological roles of this enzyme are not well understood due to a lack of chemical tools that enable its study. Herein we have identified phenylarsonic acids as general scaffolds which inhibit PHPT1 activity. Notably, phenylarsonic acids can be embedded into peptide sequences, providing the first known peptide-based inhibitors of PHPT1. In a counterscreen against a small panel of phosphatases, we demonstrate that these compounds exhibit some selectivity for PHPT1. Moreover, we show that these compounds exhibit mixed inhibition. We provide evidence that reduction of the phenylarsonic acids <i>in situ</i> by reducing agents like dithiothreit2026-01-01T00:00:00Z2026 Feb2026-07-16T06:41:31.126Z2026-07-09T10:41:21.916ZS-EPMC129157104170646610.1039/d5dt03009a