Exo-affinity labeling agents as inactivators of protein tyrosine phosphatases: Exploiting/exploring/creating covalent chemistry/reactions outside the active site

Protein tyrosine phosphatases (PTPs) are a class of enzymes that play important roles in the regulation of many mammalian signaling pathways. A number of different PTPs are potential medicinal targets for the treatment of cancer, type 2 diabetes, and autoimmune diseases. The active sites of all PTPs are highly homologous and it has proven challenging to develop selective inhibitors against individual members of this enzyme family. Here we describe the design, synthesis, and characterization of exo-affinity labeling agents for the inactivation of PTPs. These agents combine phosphotyrosine isosteres with biocompatible electrophiles such as thioester groups to react with residues outside the active site. This approach has the potential to exploit differences outside the active sites of the PTPs to yield selective and potent inactivators.