GRANT 19

The Kyba group has an ongoing research program to discover chemical inhibitors of the DUX4 protein. This work is directed towards screening and studying more complex compounds than we have evaluated previously, with the objective of discovering a compound that inhibits DUX4 primary activity, as opposed to compounds that inhibit downstream pathways. These are chemically synthesized, but more similar to natural products than to conventional drugs and have been identified through a screen of a library of complex compounds at the Broad Institute at MIT, and to develop these leads in our laboratories here in Minnesota.

Summary of Results The Kyba laboratory has screened a ~35,000 compound chemical library for inhibitors of DUX4, the protein that is responsible for muscle deterioration in FSHD. They have identified several clusters of related compounds that are suitable for follow up medicinal chemistry to investigate potential as new drugs for FSHD. In the last stage of this research, they have prioritized compounds for follow up, and designed chemical synthesis routes, for the top 3 compounds. In the next phase of this research, they will synthesize one of these compounds, together with a diversity of related compounds, for further study on the inhibition of DUX4, and for testing in animals.