Nicholas Tonks, Professor of Cancer Research, Cold Spring Harbor Cancer Center, Cold Spring Harbor, NY, will give a talk on "Protein Tyrosine Phosphatases and the regulation of cell signaling: from basic research to new therapeutics."

ABSTRACT 

The protein phosphatases are critical, specific regulators of signaling that serve an essential function, in a coordinated manner with the protein kinases, to determine the response to a physiological stimulus. My laboratory takes a multidisciplinary approach to study the structure, regulation and function of the protein tyrosine phosphatase (PTP) family of enzymes, to illustrate their fundamental importance to the control of signal transduction under normal and pathophysiological conditions. As functional studies have established links to disease, the PTPs have been garnering attention as potential therapeutic targets; however, they remain a largely untapped resource for drug development.

A focus of the lab is PTP1B, the prototypic member of the PTP family that I discovered ~30 years ago. It is a validated target for diabetes and obesity, as well as HER2-positive cancer, and as such has been the subject of extensive drug discovery efforts. PTP1B is a challenging target for drug development, which led industry to conclude that the members of the PTP family are “undruggable”. Consequently, new approaches are required to exploit this important target effectively and reinvigorate drug discovery efforts.

Now, the detailed understanding of the structure and function of PTP1B, which we have generated in an academic setting, is revealing new approaches to the development of small molecule drug candidates. This includes small molecules that harness the physiological regulation of PTP function by reversible oxidation, as well as allosteric inhibitors that stabilize an inactive conformation of PTP1B that is encountered in the absence of substrate and chelate copper specifically. These studies have opened up unanticipated ways to modulate the activity of critical signaling pathways in vivo. The application of these inhibitors is now revealing new functions of PTP1B and suggesting new indications in which these molecules may be applied for therapeutic benefit.