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Protein tyrosine phosphatases (PTPs), which catalyze the dephosphorylation of phosphotyrosine in protein substrates, are important cell-signaling regulators, as well as potential drug targets for a range of human diseases. Chemical tools for selectively targeting the activities of individual PTPs would help to elucidate PTP signaling roles and potentially expedite the validation of PTPs as therapeutic targets. We have recently reported a novel strategy for the design of non-natural allosteric-inhibition sites in PTPs, in which a tricysteine moiety is engineered within the PTP catalytic domain at a conserved location outside of the active site. Introduction of the tricysteine motif, which does not exist in any wild-type PTP, serves to sensitize target PTPs to inhibition by a biarsenical compound, providing a generalizable strategy for the generation of allosterically sensitized (as) PTPs. Here we show that the potency, selectivity …