As expected, aryl vinylsulfonates were able to inhibit several PTPs after treatment with 100 μM compound for one hour (Figure ). Phenyl vinyl sulfone (1) showed very little activity against every phosphatase except HePTP. In general, vinylsulfonates on bulkier scaffolds (compounds 3-6) showed increased potency. However, intact protein mass spectrometry revealed that these molecules were labeling other residues in addition to the catalytic cysteine, as demonstrated by the existence of protein species with more than one adduct (Figure , top panel, Figure , and Figure ). Although the bulkier scaffolds were more potent inhibitors, they did not show enhanced selectivity for the active site, suggesting that the intrinsic reactivity of the vinylsulfonate was obscuring any effects of scaffold structure on binding (Figure ). We note that off-target covalent labeling is more prevalent in our assays than in the original report of PVSN. This can be attributed to the fact our assays were done at pH 7.5, whereas PVSN and PVS were previously characterized at pH 6. Labeling of PTP1B by compound 2 was greatly attenuated at pH 6 in our assay (Figure , bottom panel). Lower pH allows for differentiation of the active site Cys residue from off-target Cys residues, due to its lower pKa, but these conditions could limit labeling applications on intact cells. A survey of published reports showing electrophilic labeling of PTPs in cell lysates revealed that most experiments were conducted between pH 5.5 and 6. These observations suggest that selective active site labeling of PTPs at physiological pH will require less reactive molecules with higher affinity for the active site.