B.S. 1995, Chemistry, University of Utah
Ph.D. 2000, Massachusetts Institute of Technology. Mentor: Stephen J. Lippard
2000-2003, Department of Pharmaceutical Chemistry, University of California, San Francisco, NIH Postdoctoral Fellow. Mentor: Charles S. Craik
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.
Understanding the biological action of metal-based drugs
While the majority of drug molecules are organic compounds, several very successful drugs contain metal ions. Certainly the most well-know (and well-studied) example is cisplatin, a platinum containing anticancer agent, but other examples include auranofin, a gold-containing antiarthritic agent; Pepto-BismolÂ®, a bismuth-containing treatment for gastrointestinal problems; and imaging agents such as magnevist (a gadolinium-based MRI contrast agent) and cardiolyte (a technetium-based radioimaging agent). In our lab, we have been studying the ability of auranofin and auranofin analogs to inhibit enzyme activity as one possible mechanism of action in the body. Au(I)-based compounds such as auranofin inhibit thiol-dependent enzymes, and we have demonstrated that, by tuning the ligands bound to the Au(I) ion, we can tune the selectivity and potency of the Au(I)-mediated inhibition. The relative potencies and selectivities of the new complexes hold up not only in vitro but also in vivo.
Designing redox sensors
A recent area of emphasis for our lab is the development of fluorogenic chemical probes that can be used to image the production of redox active species in vivo. Our first efforts in this field are aimed at developing hydrogen peroxide sensors that can be delivered to a specific subcellular location (i.e. the cell surface, the cytosol, the mitochondria, etc.) and at developing hydrogen sulfide sensors based on fluorogenic organometallic compounds.