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Accession Number:
AD1089426
Title:
The Therapeutic Effect of the Antitumor Drug 11 Beta and Related Molecules on Polycystic Kidney Disease
Corporate Author:
MASSACHUSETTS INSTITUTE OF TECHNOLOGY Cambridge United States
Report Date:
2019-12-01
Abstract:
This project aimed to develop synthetic multifunctional compounds as therapeutics for polycystic kidney disease PKD. In collaboration with the Somlo group at Yale University, we have provided extensive evidence that two parent compounds, 11beta-dichloro and 11beta-dipropyl, are effective at preventing and delaying cystic growth in two different mouse models of PKD. One arm of the project focused on the synthesis of new molecules from the 11beta family, which informed, through a structure-activity study, the key molecular features required for activity and provided additional hints about the mechanism of action. A second arm of the project focused on the development of a cell culture model that could be used to screen the new molecules for improved efficacy and selectivity such molecules could be then validated in the established PKD mouse models and pave the way towards their preclinical and clinical development. Both research arms were accomplished during this four-year long grant. Of the 6 new compounds we synthesized, one 11beta-dimethyl had activity comparable with11beta-dipropyl, while being a smaller molecular species. Among cell culture models, we investigated the porcine line LLC-PK1 and the murine line mIMCD3 and their respective PKD1 null counterparts. Both lines showed good promise for toxicity assays, when coupled with more advanced cell viability reporters e.g., the ratio metric assay MultiTox-Glo. During the last funding period, we also investigated the role of hypoxia in modulating the toxic effect of 11beta these studies are still ongoing. Mechanistically, we have generated data both in cell culture and in animal models that clearly indicate that the antioxidant vitamin E is a potent inhibitor of the 11beta compounds toxicity, confirming that the mechanism of action involves the generations of oxidative stress.
Descriptive Note:
Technical Report,30 Sep 2015,29 Sep 2019
Pages:
0033
Distribution Statement:
Approved For Public Release;
File Size:
1.45MB
