We were surprised to observe drastically different degrees of covalent inhibition across the eight classical PTP catalytic domains included in our experiments, despite the use of a simple phenyl scaffold (Figure ). Whereas HePTP, SHP1, and TCPTP were generally inhibited the most by compounds in the phenyl-electrophile series, other PTPs such as CD45, CD148, and YopH were not readily inhibited. These data suggest that the catalytic cysteine residues of individual phosphatases either have different reactivity or accessibility. These phosphatases also showed significantly different intrinsic catalytic activities in the absence of any inhibitor, consistent with previous observations (Figure ). The susceptibility to covalent inhibition showed a roughly inverse correlation with intrinsic catalytic activity (Figures ). The underlying molecular basis for this inverse correlation between covalent inhibition and catalytic activity is currently unclear. It could reflect the possibility that the rate-limiting step in the tyrosine phosphatase catalytic cycle is hydrolysis of the phospho-enzyme intermediate, as opposed to the initial nucleophilic attack by the catalytic cysteine residue, as suggested previously (Figure ). Alternatively, the ligand on-rates may be too slow to efficiently access the active sites of the highly active phosphatases, which have very fast WPD-loop closure rates. Scaffold exploration reveals global trends in tyrosine phosphatase covalent inhibition.