Methods and compositions for modulating splicing

Abstract

Described herein are small molecule splicing modulator compounds that modulate splicing of mRNA, such as pre-mRNA, encoded by genes, and methods of use of the small molecule splicing modulator compounds for modulating splicing and treating diseases and conditions.

1 .- 170 . (canceled) 
     
     
         171 . A method of treating a condition or disease associated with aberrant splicing in a human subject in need thereof, comprising administering an effective amount of a pharmaceutical composition to the subject, the pharmaceutical composition comprising:
 (a) a therapeutic agent, wherein the therapeutic agent is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof:   
       
         
           
           
               
               
           
         
         wherein, 
       
       
         
           
           
               
               
           
         
         ring Q is 
       
       
         
           
           
               
               
           
         
       
       wherein ring P is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
 X is —NR 3 —; 
 R 3  is methyl; 
 Z is CR 7 ; and R 7  is H or D; 
 W is substituted or unsubstituted C 1 -C 4  alkylene, or substituted or unsubstituted C 1 -C 4  heteroalkylene; 
 R is H; 
 R 15  and R 18  are each independently selected from H and methyl; 
 R 16  and R 17  are each H; 
 a is 0; b is 0; c is 1; d is 1; and 
 wherein the compound of Formula (IV) has a stereochemical purity of at least 80%; and 
 (b) a pharmaceutically acceptable carrier; 
 wherein the condition or disease is a condition or disease of the brain or the central nervous system (CNS); 
 wherein an effective amount of the therapeutic agent penetrates the blood brain barrier (BBB) when administered to the subject; and 
 wherein the therapeutic agent modulates splicing at a splice site sequence of a pre-mRNA in a cell of the subject thereby treating the condition or disease. 
 
     
     
         172 . The method of  claim 171 , wherein the pharmaceutical composition is administered orally. 
     
     
         173 . The method of  claim 171 , wherein the condition or disease of the brain or the CNS is Huntington's Disease. 
     
     
         174 . The method of  claim 171 , wherein the therapeutic agent has a cell viability IC50 of at least 50 nM and a therapeutic index (LD50/ED50) of at least 50. 
     
     
         175 . The method of  claim 174 , wherein the therapeutic agent has an IC50 viability/EC50 protein splicing value of at least 50. 
     
     
         176 . The method of  claim 171 , wherein the pharmaceutical composition comprises from 1 to 1000 mg of the therapeutic agent. 
     
     
         177 . The method of  claim 171 , wherein a ratio of (unbound brain AUC)/(unbound plasma AUC) reaches at least about 0.1 after administering the effective amount of the pharmaceutical composition. 
     
     
         178 . The method of  claim 171 , wherein a ratio of (unbound brain AUC)/(unbound plasma AUC) of the therapeutic agent reaches at least about 0.1 in mouse when the therapeutic agent is administered to a mouse at 3 mg/kg via intraperitoneal injection once daily or twice daily. 
     
     
         179 . The method of  claim 171 , wherein a ratio of (unbound brain AUC)/(unbound plasma AUC) of the therapeutic agent reaches at least about 0.3 in mouse when the therapeutic agent is administered to a mouse at 3 mg/kg via intraperitoneal injection once daily or twice daily. 
     
     
         180 . The method of  claim 171 , wherein splicing of the pre-mRNA at the splice site sequence is increased after administering the effective amount of the pharmaceutical composition. 
     
     
         181 . The method of  claim 171 , wherein nonsense-mediated degradation (NMD) of a messenger RNA (mRNA) processed from the pre-mRNA is modulated and expression of a protein encoded by the mRNA processed from the pre-mRNA is decreased. 
     
     
         182 . The method of  claim 171 , wherein the splice site sequence comprises a sequence selected from the group consisting of NGAgunvrn, NHAdddddn, NNBnnnnnn, and NHAddmhvk; wherein N or n is A, U, G or C; B is C, G, or U; H or h is A, C, or U; d is a, g, or u; m is a or c; r is a or g; v is a, c or g; k is g or u. 
     
     
         183 . The method of  claim 171 , wherein the splice site sequence comprises CAGguacug, AAGguaaau, AGAguaagu, CUGgugagu, ACCgugagu, or AGAguaagg. 
     
     
         184 . The method of  claim 171 , wherein the splice site sequence comprises AGAguaagg. 
     
     
         185 . The method of  claim 171 , wherein ring P is heteroaryl selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein each R B  is independently selected from cyano, halogen, hydroxy, substituted or unsubstituted C 1-6  alkyl, —OCH 3 , —OCD 3 , substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, substituted or unsubstituted C 1-6  alkoxy, substituted or unsubstituted C 3-7  cycloalkyl, substituted or unsubstituted C 2-8  heterocycloalkyl, heteroaryl, substituted or unsubstituted heterocycloalkyl-C 1-6  alkyl, substituted or unsubstituted C 1-6  alkyl-aryl, substituted or unsubstituted C 1-6  alkyl-heterocycloalkyl, substituted or unsubstituted C 1-6  alkyl-heteroaryl, substituted or unsubstituted C 1-6  alkoxy-aryl, substituted or unsubstituted C 1-6  alkoxy-heterocycloalkyl, substituted or unsubstituted C 1-6  alkoxy-heteroaryl, and C 1-6  alkoxy substituted with hydroxy, C 1-6  alkoxy, amino, mono-C 1-6  alkylamino and di-C 1-6  alkylamino; and m is 0, 1, 2, or 3. 
     
     
         186 . The method of  claim 171 , wherein ring P is heteroaryl selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         187 . The method of  claim 171 , wherein ring P is heteroaryl selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         188 . The method of  claim 171 , wherein W is substituted or unsubstituted C 1 -C 4  alkylene. 
     
     
         189 . The method of  claim 171 , wherein W is —CH 2 CH 2 — or —CH 2 CH 2 CH 2 —.