Inhibition of DUX4 Expression Using Bromodomain and Extra-Terminal Domain Protein Inhibitors (BETi)
Updated patent 2018 Francis M. Sverdrup
Repost
https://patents.justia.com/patent/20180050043
While pulse treatment with most BETi allows recovery of the lineage-specific MYH2 gene expression in myotubes, it is surprising that the BETi RVX-208 did not suppress MYH2 expression upon continuous exposure. FIGS. 17A and 17B demonstrate that 20 μM RVX-208 does not reduce MYH2 expression while significantly reducing DUX4 target gene expression. RVX-208 is different than other known BETi in that it preferentially binds the second of the two bromodomains present in BET proteins (BD2). The functional consequence is that fewer genes are affected by RVX-208. We have shown by two methods (pulse exposure-recovery with inhibitors such as I-BET762 and (+)-JQ1 and continuous exposure to the unique pharmacophore RVX-208) that blocking DUX4 expression via BET inhibition can be achieved without significant unwanted effects on muscle cell differentiation