Identification of Stabilizers of Multimeric Proteins

Abstract

Disclosed herein are compounds and compositions thereof which find use in increasing stability of TTR tetramers reducing its tendency to misfold and form aggregates. Also provided herein are methods for using these compounds and compositions for increasing stability of TTR and thereby decreasing aggregate formation by TTR. Also disclosed herein are methods to screen for candidate compounds that increase stability of TTR. Also disclosed herein are heterobifunctional compounds that include a TTR binding compound connected to a targeting moiety via a linker, for use in disrupting PPIs of a target protein.

1 - 89 . (canceled) 
     
     
         90 . A compound of Formula (V), (VI), or (VII) 
       
         
           
           
               
               
           
         
         wherein R 8 , R 10  and R 13  are independently one or more groups, each R 8 , R 10  and R 13  is independently selected from hydrogen, an alkyl, an aryl, an alkoxy, an aryloxy, an acetyl, a carboxy, a formyl, an amido, a hydroxyl, a heterocyclic group, a halo, a nitro and a cyano; and 
         R 7 , R 9 , R 11  and R 12  are independently selected from hydrogen, an alkyl, an aryl, an acetyl, a carboxy, a formyl, an amido, a sulfonyl, a sulfinyl, a thio, an acetyl and an amino 
       
     
     
         91 . The compound of claim
   90 , wherein each R 8 , R 10  and R 13  independently selected from a benzyloxy group, a trifluoromethyl, a halo, a carboxy, a formyl, a methyl, a hydroxyl, a methoxy and a phenyl.   
     
     
         92 . The compound of claim
   90 , wherein R 7 , R 9 , R 11  and R 12  are independently selected from methylsulfinyl, methylsulfonyl, a lower alkyl thioether, SH and a lower alkyl.   
     
     
         93 . The compound of claim
   90 , wherein at least one R 8 , R 10  and R 13  group is selected from a carboxy, a formyl and a hydroxy, and is attached at the 2-position of the phenyl ring.   
     
     
         94 . A compound of Formula (IV) 
       
         
           
           
               
               
           
         
         wherein R 6  is selected from hydrogen, an alkyl, an aryl, an alkoxy, an aryloxy, an acetyl, a carboxy, a formyl, an amido, a hydroxyl, a heterocyclic group, a halo, a nitro and a cyano. 
       
     
     
         95 . The compound of  claim 94 , wherein R 6  is selected from a benzyloxy group, a trifluoromethyl, a bromo, a chloro, a methyl, a hydroxyl, a methoxy and a phenyl. 
     
     
         96 . A method of decreasing TTR amyloid fibril formation, the method comprising contacting TTR with the compound of  claim 90 , wherein the contacting decreases TTR amyloid fibril formation. 
     
     
         97 . A method of decreasing TTR amyloid fibril formation, the method comprising contacting TTR with the compound of  claim 94 , wherein the contacting decreases TTR amyloid fibril formation.