The Therapeutic Effect of the Antitumor Drug 11beta and Related Molecules on Polycystic Kidney Disease
Abstract
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a familial disease that primarily affects the kidney and liver. The disease causes abnormal growth to fluid-filled sacs (cysts) in the kidney and liver that grow over decades. People affected with this disease develop a number of symptoms related to the growth of these cysts that include high blood pressure, a sensation of fullness and pain in the abdomen, and chronic kidney disease that eventually leads many patients to need either dialysis or kidney transplantation. Over 600,000 people are affected by this disease in the United States. Currently, there is no effective, Food and Drug Administration-approved therapy for ADPKD. The genes mutated in causing ADPKD have been identified, and much basic science research has been done to improve our understanding of what causes this disease in people. Based on this body of research, we now propose to investigate some avenues toward potential treatment. This grant application is intended to develop molecules that have the potential to be useful in clinical trials in patients. To achieve this goal, we combine the efforts of two expert groups to both design and optimize the potential medicinal molecules and to test them out for effectiveness in ADPKD by studying them in cultured cells and engineered mouse models that closely represent the human disease. We have strong preliminary evidence that suggests that cystic cells, the cells whose proliferation leads to ADPKD, can be selectively killed when treated with a novel, synthetic drug candidate called 11beta-dichloro. We showed this effect in two distinct mouse models of ADPKD. Our idea is that 11beta-dichloro targets the cystic cells specifically by taking advantage of their abnormal metabolism that makes them susceptible to some forms of cellular injury, called oxidative stress and the unfolded protein response. We believe we can take advantage of these cyst cell vulnerabilities to slow down the growth of cysts and therefore help treat ADPKD. However promising, the 11beta-dichloro molecule has chemical features that can cause DNA damage, which is likely to cause undesirable side effects in clinical development. Therefore, we have synthesized an improved analog, called 11beta-dipropyl, which closely resembles 11beta-dichloro, but does not damage DNA. We have also shown that 11beta-dipropyl is effective in slowing polycystic kidney disease in a mouse model of ADPKD. This proposal focuses on the preclinical development of theses 11beta compounds, using 11beta-dipropyl as a starting point. We propose two specific aims. In Aim 1, we will first validate the 11beta-dipropyl compound in an adult mouse model of ADPKD that is more reminiscent of the human disease. Then, we will investigate more closely the mechanism of action of 11beta compounds in cystic cells, focusing on the pathways we suspect are responsible for the efficacy and selectivity of the 11beta compounds, such as induction of oxidative stress, induction of the unfolded protein response, and activation of specific pathways resulting in cell death. In Aim 2, we will chemically synthesize a series of analogs of 11beta-dipropyl, which will allow us to understand which molecular features are responsible for the anti-ADPKD effect of the compound. These studies will allow us to synthesize a better version of the compound that is more effective, more selective, and has more drug-like features such as favorable solubility and metabolism. The efficacy of the new compounds will be investigated in cell culture and validated in the mouse models of ADPKD, with the eventual goal of selecting a lead drug candidate to take into the clinic. Overall, the proposed research will provide insight on a novel strategy to target ADPKD, as well as provide potential drug candidates for ADPKD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510365
Entities
People
- John Essigmann
Organizations
- Harvard University
- United States Army