Chemical probes for visualizing PTP activity
Protein tyrosine phosphatases (PTPs) play critical roles in cellular signaling, regulating tyrosine phosphorylation through hydrolysis of the tyrosine phosphate in a temporally, spatially and regioselectively controlled manner. In contrast to their counterparts, the protein tyrosine kinases (PTKs), the substrate selectivity, biological regulation and specific roles of PTPs are relatively poorly understood. However, aberrant phosphotyrosine-dependent cellular signaling plays an important role in many human diseases, including cancer, diabetes and autoimmunity. PTK-targeted drugs have hit the market with considerable success as anticancer agents, but no
PTP-targeted drugs have been developed to date. In this project, our aim is to develop novel PTP-targeted chemical probes that can be used to elucidate the biological roles of PTPs and can serve as lead compounds in the development of PTP-targeted therapeutics. For example, we designed the phosphocoumaryl amino acid pCAP as a fluorogenic phosphotyrosine mimic. This probe has been invaluable in allowing us to profile the substrate selectivity of PTPs, perform several high-throughput screens to identify novel PTP inhibitors, and visualize PTP activity both directly in cells and in cell lysates through polyacrylamide gel electrophoresis. Current work includes characterizing and optimizing the new inhibitors we have discovered and developing novel activity-based probes for PTPs.