Kabonick, Seth *, Noah Smith , Anne Reeve, and Sarah Codd Messiah University, Mechanicsburg, PA 17055. Synthesis of novel hydroxychalcone derivatives as potential inhibitiors of protein tyrosine phsophatase 1B.- Protein phosphatases have been considered a potential target for drug-based therapy since their discovery. Mutations of phosphatases found in cell signaling pathways have been linked to type II diabetes, obesity, and certain types of cancer. One of these phosphatases, protein tyrosine phosphatase 1B (PTP1B), functions as a negative regulator of the insulin pathway. A gene knockout study in mice confirmed that mutations to this protein result in a dampened insulin sensitivity. Previous attempts at competitive inhibition through drug-based therapy have been unsuccessful due to the highly conserved active site across the phosphatase family. This study explores the plethora of natural products available as potential inhibitors for PTP1B in hopes of designing a molecular scaffold to generate site-specific inhibitors. Chalcones and stilbenes are two compound families that have previously exhibited inhibitory binding. Hydroxychalcone derivatives, specifically those in the para position, show promise as a drug scaffold for specific active site inhibitors. In addition, isoprenyl groups attached to branching aromatic rings have a significantly higher binding affinity to PTP1B and a lower IC50. Initial in silico results showed moderate to high binding affinities for a small hydroxychalcone library. Currently, enzyme activity levels in the presence of these hydroxychalcones are determined using absorbance assays. Duplicate assays are performed with detergent to account for non-specific inhibition caused by aggregation. Preliminary assays using commercially available hydroxychalcones display slight to moderate inhibition of PTP1B at the active site. In future studies, twelve hydroxychalcones will be synthesized and introduced into an absorbance assay to evaluate their potential as a scaffold for PTP1B specific inhibitors. (1) Poster Link