School of Pharmacy UNIVERSITY OF WISCONSIN - MADISON Research Drug Discovery: a) We are developing small molecules that can selectively remove disease-causing proteins in cells and animal models. These small molecules can be used as probes to knock out proteins and therapeutics to treat human diseases. b) We are also developing small molecule ligands for carbohydrate binding proteins that are secreted from the cells or on the outer membrane. These proteins are essential for cell-cell communications and many diseases, such as cancers and vascular diseases. c) We develop various cell-based and biochemical assays to evaluate the pharmacological properties of the above small molecules such as potency, selectivity, and stability. We also design assays to study the detailed cellular mechanisms of these novel small molecules such as how they induce the ubiquitination, degradation and other cellular changes. Organic Synthesis: We are interesting in advancing glycoscience by streamlining the synthesis of carbohydrates through the development of novel technologies (e.g. site-selective functionalization, de novo synthesis of bacterial sugars, automated synthesis, electrochemical synthesis, etc.). We are also interested in developing novel reactions for the synthesis of carbo- and heterocycles that are present in diverse bioactive polycyclic natural products and pharmaceutical agents. These reactions can be used for the optimization of pharmacological properties of small molecules such as potency, selectivity, stability, and solubility for treating various human diseases. Chemical Biology and Mechanism of Action of Bioactive Compounds: We are interested in dissecting the complex biological pathways by novel small molecule probes. We are currently developing small molecules that can selectively modulate protein stability and epigenetic markers. For example, we have developed small molecules that can selectively downregulate PCSK9 proteins, which may have the potential for treating hyperlipidemia. We have also developed small molecules that can selectively degrade estrogen receptors, which may have the potential for treating certain types of breast cancers. We employ a variety of chemical and biological tools to study the detailed mechanism of action of bioactive compounds.