Aberrant cellular signaling stemming from altered protein tyrosine phosphorylation is a major contributing factor tohuman diseases including cancer, diabetes, and autoimmune disorders. Consequently, anomalous cellular events driven by defective protein tyrosine phosphorylation afford tremendous opportunities for targeted intervention. Success for such targeted approach is evident by the abundance of kinase-based therapeutics that have become important treatment modalities. Given the reversible nature of protein tyrosine phosphorylation, there is great potential to manipulate disease biology at the level of protein tyrosine phosphatases (PTPs). However, despite increasing interest in PTPs, they still remain largely an underexploited target class. Indeed, the PTPs are exceptionally challenging targets for drug discovery.Among major challenge of targeting PTPs for drug discovery is the general lack of PTP-specific small molecule probes for functional interrogation, target validation, and therapeutic development. In this presentation, I discuss several approaches for the acquisition of highly potent and selective PTP inhibitors with efficacious in vivo activity. Potent and specific PTP inhibitors facilitate functional analysis of the PTPs in complex signaling pathways and may provide unique solutions for the treatment of many human diseases.

Approaches to “undruggable” tyrosine phosphatase targets

ACS Fall 2021

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