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The disease has recently been linked to the gene DUX4, which encodes a protein that is toxic to muscle progenitor cells. We have screened a chemical library of 200,000 compounds and identified 640 compounds with a protective effect on cells expressing DUX4. We propose to identify within this set, those compounds with the highest likelihood of being developed into drugs that can block DUX4. We will begin preliminary preclinical development by synthesizing key compounds and related derivatives, and screening these for activity on DUX4-expressing cells. We will test the most promising of these in mice that carry the DUX4 gene, evaluating their ability to prevent damage caused by DUX4 expression. The goal is to identify compounds suitable for development into drugs for the treatment of FSHD. We propose a two-year program directed towards identifying 2-3 chemical series suitable for focused development.
Specific Aim 1. To supplement secondary screening data. Our hits, and additional compounds (from Aim 2) will be taken through two additional assays: they will be tested (1) for inhibition of toxicity in a human DUX4-inducible cell line, and (2) for inhibition of non-toxic phenotypes of DUX4 that arise upon low level expression in C2C12 myoblasts. This data will be used to prioritize chemical series for continued and future development.
Specific Aim 2. To identify and expand chemical series within our hit set. We will select several chemical series for development, based on desirable chemical properties and feasibility of chemical synthesis. These will be purchased, along with additional chemicals within the same chemical series such as are available, evaluated by mass spectrometry and NMR to validate identity, and tested in our cell-based assays to evaluate the feasibility of structure-activity relationship studies within the series. We will then synthesize key compounds to validate chemical identity, and a limited number of derivatives to provide insight into which lead series may be most suitable for continued development.
Specific Aim 3. To test selected compounds against DUX4-mediated toxicity in mice. Using our knowledge of medicinal chemistry, a small set of compounds will be selected based on desirable chemical properties and priority of their chemical series. They will be assayed for their ability to reduce the toxic effects of systemic expression of DUX4, and for their ability to protect regenerating muscle from the effects of DUX4. Efficacy in these assays, while not critical at this stage, will be considered favorable for the continued development of a chemical series. Preliminary pharmacokinetics data will be obtained from serum concentrations of injected compounds.
— Michael Kyba
This funding supplements an R21 grant Michael Kyba, an Associate Professor at the Lillehei Heart Institute, was recently awarded by NIH/NINDS. The 2-year grant allows additional resources to be put on this project in order to move it forward quickly. The project is being done in collaboration with a medicinal chemist at the Institute for Therapeutics Discovery and Development at the University of Minnesota, an investigator with experience at bringing drugs from the current stage all the way to clinical trials.