Modularly assembled small molecules for the treatment of myotonic dystrophy type 1

Abstract

Transcriptomes provide a myriad of potential RNAs that could be the targets of therapeutics or chemical genetic probes of function. Cell permeable small molecules, however, generally do not exploit these targets, owing to the difficulty in the design of high affinity, specific small molecules targeting RNA. As part of a general program to study RNA function using small molecules, we designed bioactive, modularly assembled small molecules that target the non-coding expanded RNA repeat that causes myotonic dystrophy type 1 (DM1), r(CUG)exp. Herein, we present a rigorous study to elucidate features in modularly assembled compounds that afford bioactivity. Different modular assembly scaffolds were investigated including polyamines, α-peptides, β-peptides, and peptide tertiary amides (PTAs). Based on activity as assessed by improvement of DM1-associated defects, stability against proteases, cellular permeability, and toxicity, we discovered that constrained backbones, namely PTAs, are optimal.

What is claimed is: 
     
         1 . A dimeric r(CUG) exp  binding compound of formula (I)
   H—Y—H  (I)
   wherein H is a group of formula   
       
         
           
           
               
               
           
         
         wherein a wavy line indicates a position of bonding, and 
         wherein Y is a bifunctional linker comprising at least two primary or secondary amino groups, and optional further comprising additional amino, carboxamido, or peptidyl groups; 
         or a pharmaceutically suitable salt thereof. 
       
     
     
         2 . The compound of  claim 1  wherein Y is a 1,ω-diaminoalkane, optional further comprising additional amino, carboxamido, or peptidyl groups. 
     
     
         3 . The compound of  claim 1  wherein Y further comprises one or more α-peptidyl segment, β-peptidyl segment, polyamino segment, peptidyl tertiary amide segments, or any combination thereof. 
     
     
         4 . The compound of  claim 1  wherein Y is selected from the group consisting of 
       
         
           
           
               
               
           
         
         wherein wavy lines each indicate a point of bonding to a respective group H, and 
         n is a whole number ranging from 1 to about 20. 
       
     
     
         5 . The compound of  claim 1 , of formula 
       
         
           
           
               
               
           
         
       
     
     
         6 . A method of disrupting the r(CUG) 12 -MBNL1 complex, comprising administering an effective amount of a compound of any one of  claims 1 - 5  to a living mammalian cell. 
     
     
         7 . The method of  claim 6  wherein the living mammalian cell is in the body tissue of a human patient. 
     
     
         8 . A method of treatment of myotonic dystrophy type 1 in a human patient, comprising administering an effective amount of a compound of any one of  claims 1 - 5  to the patient.