This project aims to develop and validate synthetic multifunctional compounds as therapeutics for polycystic kidney disease PKD. In collaboration with the Essigmann lab at MIT, we have shown that two parent compounds, 11B-dichloro and 11B-dipropyl, are effective in preventing and delaying cyst growth in two different orthologous mouse models of PKD. To guide the development of new compounds, the mechanism by which 11B compounds achieve their efficacy and selectivity against cystic cells is being investigated. One arm of the project focuses on the synthesis of new molecules in the 11B family, which will inform, through structure-activity studies, the key molecular features required for activity and provide additional hints about mechanism of action. A second arm of the project focuses on the development of a cell culture model that can be used to screen the new molecules for improved efficacy and selectivity such molecules will be then validated in the established PKD mouse models and pave the way towards their preclinical and clinical development. During the last funding period, we successfully synthesized 0.5 g of 11B-dipropyl which is beginning testing in the adult onset model of PKD. We produced and studied novel epithelial cell line models of 11B action. We established potentially novel roles for mitochondrial function and the unfolded protein response in PKD pathogenesis and 11B action.