The Therapeutic Effect of the Antitumor Drug 11beta and Related Molecules on Polycystic Kidney Disease
Abstract
This project aims to develop synthetic multifunctional compounds as therapeutics for polycystic kidney disease (PKD). In collaboration with Somlo group at Yale University, we have already shown that two parent compounds, 11-dichloro and 11-dipropyl, are effective at preventing and delaying cystic growth in two different mouse models of PKD. One arm of the project focuses on the synthesis of new molecules from the 11 family, which will inform, through a structure-activity study, the key molecular features required for activity and provide additional hints about the 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 continued the work on validating cell culture models that recapitulate the biological consequences of 11 compounds. The pig kidney cell lines derived from LLC-PK1 show good promise for toxicity assays, when coupled with the total cellular ATP measurements (Cell-Titer Glo Assay). We also investigated aspects of the mechanism of toxicity in these cell culture models. Additionally, we completed the synthesis of 5 new 11 analogs, and a 6th analog will be completed soon. The new compounds were tested for efficacy and selectivity in cell culture, providing new structure-activity information. Moreover, our collaborators at Yale University continued their work probing the mechanism of toxicity of 11 compounds in animals (induction of mitochondrial ROS) and testing the 11-dipropyl compound in the adult mouse model of PKD; only preliminary data are available at this point.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2017
- Accession Number
- AD1050842
Entities
People
- Bogdan Fedeles
- John Essigmann
- Robert Croy
Organizations
- Massachusetts Institute of Technology