Protein tyrosine phosphorylation is a dynamic and critical regulatory mechanism involved in most intracellular signal pathways. Aberrant protein tyrosine phosphorylation has been linked to the etiology of many human diseases including cancer, diabetes/obesity, neurodegenerative and autoimmune disorders. Notable success has been achieved in targeting abnormal signaling pathways mediated by protein tyrosine phosphorylation, with more than two dozen of small molecule tyrosine kinase inhibitors already in the clinic. As major regulators of protein tyrosine phosphorylation, protein tyrosine phosphatases (PTPs) have been garnering attention as potential therapeutic targets. Unfortunately, these targets are often characterized as being ‘undruggable’ and remain largely an untapped resource. In fact, PTP-based drug discovery programs have historically been shrouded with difficulty in inhibitor selectivity and bioavailability, both of which are related to the intrinsic PTP active site properties.

We are working on a novel approach for the design of potent and specific PTP inhibitors by tethering appropriately functionalized moieties to a nonhydrolyzable pTyr mimetic in order to engage both the active site and nearby unique peripheral binding pockets. By targeting less conserved interactions outside of the pTyr-binding cleft, increased affinity and selectivity can be obtained. Several novel nonhydrolyzable pTyr mimetics have been developed over the last few years offering potential solutions to overcome the bioavailability issue that has long plagued the PTP drug discovery field. Our recent work demonstrate that these pTyr mimetic pharmacophores are sufficiently polar to bind the PTP active site, yet remain capable of efficiently crossing cell membranes, offering PTP inhibitors with both high affinity and selectivity and excellent in vivo efficacy in animal models of oncology, diabetes/obesity, autoimmunity, and tuberculosis. Current work is focused to advance our lead generation paradigm and create a ‘PTP-based drug discovery platform’ that will ultimately impact broadly the portfolio of tomorrow.