We assessed a broad range of thiol-reactive electrophilic functional groups (warheads) for their ability to target the active site cysteine of PTPs (Figure and Table ). To isolate the effect of the reactive group, we focused on compounds with a simple phenyl scaffold and assessed phosphatase inhibition using the pNPP dephosphorylation assay described above (Figure ). These experiments revealed a general rankorder for the reactivity of different warheads towards PTPs (Figure and Table ). As expected, there was a wide range of potency across different warheads. Vinylsulfonate (compound 2) was one of the most reactive warheads (Figure ). Given the hyper-reactivity of vinylsulfonates observed at physiological pH, we conclude that electrophiles with similar reactivity may also be unsuitable for PTP inhibitor or probe design. Substitution of ester linkages with amides resulted in lower reactivity for all cases (compare 2 to 10, 9 to 12, and 13 to 15), as anticipated. Chloroacetamide (compound 16), which is commonly used in fragment electrophile screening libraries, showed a small but detectable amount of phosphatase inhibition under these conditions (Figure and Table ). We reasoned that the chloroacetamide warhead would be a good starting point for fragment scaffold screening, and that the electrophile survey presented here could be used to guide late-stage tuning of compound reactivity.