Compounds for treatment of diseases related to DUX4 expression

Abstract

The present invention relates to compounds for the treatment of diseases related to DUX4 expression, such as muscular dystrophies, wherein the disease is facioscapulohumeral muscular dystrophy (FSHD). It also relates to use of such compounds, or to methods of use of such compounds.

1 . A casein kinase 1 inhibitor for use in the treatment of a disease or condition associated with DUX4 expression, wherein the casein kinase 1 inhibitor reduces DUX4 expression. 
     
     
         2 . A casein kinase 1 inhibitor for use according to  claim 1 , wherein said disease or condition associated with DUX4 expression is a muscular dystrophy or cancer, preferably wherein said disease or condition associated with DUX4 expression is a muscular dystrophy, most preferably facioscapulohumeral muscular dystrophy (FSHD). 
     
     
         3 . A casein kinase 1 inhibitor for use according to  claim 1  or  2 , characterized in that it is administered to a subject 4, 3, 2, or 1 times per day or less, preferably 1 time per day. 
     
     
         4 . A casein kinase 1 inhibitor for use according to any one of  claims 1 - 3 , wherein the casein kinase inhibitor inhibits at least casein kinase 1δ. 
     
     
         5 . A casein kinase 1 inhibitor for use according to any one of  claims 1 - 4 , characterized in that it is administered to a subject in an amount ranging from 0.1 to 1500 mg/day, preferably from 0.1 to 400 mg/day, more preferably from 0.25 to 150 mg/day. 
     
     
         6 . A casein kinase 1 inhibitor for use according to any one of  claims 1 - 5 , characterized in that it is administered orally, sublingually, intravascularly, intravenously, subcutaneously, or transdermally, preferably orally. 
     
     
         7 . A casein kinase 1 inhibitor for use according to any one of  claims 1 - 6 , wherein DUX4 expression is reduced by at least 20%, 40%, 60%, 80%, or more. 
     
     
         8 . A casein kinase 1 inhibitor for use according to any one of  claims 1 - 7 , wherein the casein kinase 1 inhibitor reduces DUX4 expression in muscle cells, immune cells, or cancer cells. 
     
     
         9 . A casein kinase 1 inhibitor for use according to any one of  claims 1 - 8 , wherein the reduction of DUX4 expression is determined using PCR or immunostaining. 
     
     
         10 . A casein kinase 1 inhibitor for use according to any one of  claims 1 - 9 , wherein the casein kinase 1 inhibitor is from the class comprising an azole core. 
     
     
         11 . A casein kinase 1 inhibitor for use according to any one of  claims 1 - 10 , wherein the casein kinase 1 inhibitor is selected from the group consisting of compounds A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, SR-3029, PF-670462, and PF-5006739. 
     
     
         12 . A composition comprising
 at least one casein kinase 1 inhibitor as defined in any one of  claims 1 - 11 , and   a pharmaceutically acceptable excipient,   for use as defined in any one of  claims 1 - 11 .   
     
     
         13 . A composition for use according to  claim 12 , wherein the composition is formulated for oral, sublingual, parenteral, intravascular, intravenous, subcutaneous, or transdermal administration, preferably for oral administration. 
     
     
         14 . An in vivo, in vitro, or ex vivo method for reducing DUX4 expression, the method comprising the step of contacting a cell with a casein kinase 1 inhibitor as defined in any one of  claims 1 - 11 , or with a composition as defined in  claim 12  or  13 . 
     
     
         15 . A method for reducing DUX4 expression in a subject in need thereof, the method comprising the step of administering an effective amount of a casein kinase 1 inhibitor as defined in any one of  claims 1 - 11 , or a composition as defined in  claim 12  or  13 .