Progress Update: The discovery of a novel small molecule inhibitor for DUX4

Report by Dr. Ozes
See grant The discovery of a novel small molecule inhibitor for DUX4

We were honored to be granted funds to use our platform technology to find potential inhibitors against DUX4. Our primary goal is to develop a direct DUX4 inhibitor and bring it to the clinic to help FSHD patients.

Using the funds we have received from the Friends of FSH Research foundation, we have successfully reached and exceeded our goal of identifying a novel inhibitor for DUX4. Using Altay’s platform technology, we performed genetic studies and identified key residues for DUX4 activity. Using these sites, we performed molecular simulations and identified a novel small molecule binding site. Next, we performed a large scale in silico screening using 2.8M compounds and identified a potent small molecule inhibitor, DX5 that inhibits DUX4’s interaction with DNA. Using structural information from our previous studies we designed 21 analogs that confirmed the activity of DX5 as well as resulted in a 2nd generation molecule, DX5001 that is 20-30 times more potent than DX5.

Importantly, we demonstrated that both compounds can rescue DUX4 dependent cell death and significantly reduce DUX4 target gene expression. The immediate next steps are to 1) demonstrate specificity to DUX4 by testing our lead compounds against PAX3/7 inhibition 2) demonstrate minimum toxicity to differentiating myoblasts, and 3) demonstrate in vivo activity by reducing DUX4 target genes.