We were able to extract other useful structure-activity relationships in relation to previously reported non-covalent inhibitors. For example, in the context of a phenyl scaffold, we found that a carboxy substitution at the 2-position reduced intrinsic reactivity, which could be useful for probe design. However, this substitution did not improve potency (Figure ). Previous reports have shown that 2-carboxy substitutions are favorable in unnatural phosphotyrosine-like substrates and non-covalent inhibitors, due to an intimate electro- static interaction with a conserved lysine residue in PTPs. In the context of covalent inhibition, the significant decrease in chloroacetamide reactivity caused by the 2-carboxy substituent likely negates beneficial binding effects of this appendage. By contrast, a 2-hydroxy substitution both modestly reduced reactivity and enhanced potency (Figure ). Non-covalent inhibitors of TCPTP and PTP1B have recently entered the clinical pipeline, and these molecules have a 2-hydroxy substitution on an aryl ring, adjacent to the phosphomimetic "head group" that lies in the same position as the electrophile in our molecules (Figure ). Our fragment library contains several thiazole-derived molecules that also reveal informative structureactivity relationships (Figure ). Compound 65, comprised of a simple thiazole scaffold, shows moderate potency towards PTPs relative to our entire library. However, amongst thiazoles, it was one of the weakest inhibitors of PTPs and showed high intrinsic thiol reactivity. Modifications to this base scaffold generally imparted increased potency against PTPs and in most cases reduced intrinsic thiol reactivity. Benzothiazole (compound 74), was both more reactive and more potent than the unsubstituted thiazole (compound 65). However, further substitution off the benzothiazole decreased intrinsic reactivity, in some cases with mild or even favorable impact on potency against PTPs (Figure ). As with phenyl-based compounds, aromatic substitutions on the thiazole resulted in increased potency (Figure ). Altering the substituent on the coupled aromatic ring further modulated PTP inhibition and thiol reactivity, as seen with compounds 71 and 73. These distal substituents also had an impact on phosphatase selectivity, as exemplified by the biased inhibition of HePTP, and to a lesser extent SHP1, by compound 71, the 4-hydroxy derivative (Figure ).