Dr. Tautz is a chemical biologist—integrating the fields of organic and medicinal chemistry, biochemistry, and molecular and cell biology—to develop small-molecule compounds that perturb and probe intracellular signaling cascades, with a focus on those that rely on the phosphorylation and dephosphorylation of signaling molecules. About one third of all proteins are transiently phosphorylated in response to distinct signaling events, and many inherited or acquired human diseases stem from abnormalities in the activities of protein kinases and protein phosphatases, the effectors of protein phosphorylation and dephosphorylation, respectively.

While efficacious therapeutics targeting protein kinases have been successfully used to treat human diseases (e.g. Gleevec, Iressa, Nexavar, Tarceva), effective strategies to target specific protein phosphatases are still elusive. Dr. Tautz’ laboratory is focused on the development of protein tyrosine phosphatase (PTP) inhibitors. These targets are challenging because they have highly conserved active sites and thus inhibitors that target the PTP catalytic site are often potent, but poorly selective. Dr. Tautz has significantly transformed conventional drug discovery strategies to substantially improve upon both the selectivity and bioavailability of potent PTP inhibitors. Novel, innovative strategies include the targeting of ‘open-state’ PTP conformations, which allows for the generation of more selective compounds, and the identification and targeting of novel allosteric sites that are distal from the PTP catalytic center. The resulting compounds are then used to study complex biological processes in cells or animal models with a resolution that is not offered by genetic approaches. Besides being invaluable tools for basic research, the chemical probes he generates also provide starting points for the development of novel therapeutics. 

Research projects:

• Regulation of MAP kinase signaling in acute leukemias through inhibition of the hematopoietic protein tyrosine phosphatase (HePTP).
• T cell activation in individuals carrying a gain-of-function mutant of the lymphoid tyrosine phosphatase (LYP), which confers increased risk for autoimmunity, including diseases like type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus.
• Inhibition of the striatal-enriched protein tyrosine phosphatase (STEP), a novel drug target in Alzheimer’s disease and schizophrenia.
• Targeting of the dual-specificity phosphatase VHR, a critical regulator in cell cycle progression in cervix cancer cells.
• Inhibitors of the SHP2 (PTPN11) phosphatase as novel therapeutics in various leukemias and other cancers.
• Inhibitors of PTP1B as potential therapeutics in breast cancers.