Compounds that participate in cooperative binding and uses thereof

Abstract

The invention features compounds (e.g., macrocyclic compounds) capable of modulating biological processes, for example through binding to a presenter protein (e.g., a member of the FKBP family, a member of the cyclophilin family, or PIN1) and a target protein (e.g., a eukaryotic target protein such as a mammalian target protein or a fungal target protein or a prokaryotic target protein such as a bacterial target protein). These compounds bind endogenous intracellular presenter proteins, such as the FKBPs or cyclophilins, and the resulting binary complexes selectively bind and modulate the activity of intracellular target proteins. Formation of a tripartite complex among the presenter protein, the compound, and the target protein is driven by both protein-compound and protein-protein interactions, and both are required for modulation of the targeted protein's activity. In some embodiments, the compounds of the invention “re-program” the binding of the presenter proteins to protein targets that either do not normally bind to the presenter protein (e.g., do not show detectable binding in mammalian cells absent the compound). In some embodiments, provided compounds “re-program” presenter protein binding to greatly enhance interaction with a particular target with which it may have some interaction absent the compound. Interactions achieved through such reprogramming result in an ability to modulate the activity of these new targets.

What is claimed is: 
     
         1 . A compound having the structure: 
       
         
           
           
               
               
           
         
         wherein: 
         A is an optionally substituted C 1 -C 20  alkyl or optionally substituted C 1 -C 20  heteroalkyl; 
         Each of L 1  and L 2  is, independently, a linker; 
         B has the structure of Formula V: 
       
       
         
           
           
               
               
           
         
         wherein: 
         X 5  is O or NR 13 ; 
         each of R 6  and R 7  is, independently, hydrogen, optionally substituted C 1 -C 6  alkyl, or R 6  and R 7  combine with the carbon atom to which they are bound to form C═O; 
         R 13  is hydrogen, or optionally substituted C 1 -C 6  alkyl, 
         R 14  is optionally substituted —(C 1 -C 6  alkylene)—C 6 -C 10  aryl; and 
         o is 1, 2 or 3. 
       
     
     
         2 . The compound of  claim 1 , wherein A has the structure of Formula IX: 
       
         
           
           
               
               
           
         
         wherein: 
         each Y is, independently selected from any amino acid, NR 20 , or 
       
       
         
           
           
               
               
           
         
         wherein each R 20  is, independently, hydrogen, or optionally substituted C 1 -C 6  alkyl; 
         each R 21  and R 22  is, independently, hydrogen, halogen, optionally substituted hydroxyl, optionally substituted amino, or R 21  and R 22  combine to form ═O; and 
         u is 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19, or 20. 
       
     
     
         3 . The compound of  claim 1 , wherein B comprises the structure: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein X 5  is O. 
     
     
         5 . The compound of  claim 1 , wherein X 5  is NR 13 . 
     
     
         6 . The compound of  claim 5 , wherein R 13  is hydrogen. 
     
     
         7 . The compound of  claim 1 , wherein R 14  is optionally substituted —(C 1 -C 2  alkylene)—C 6  aryl. 
     
     
         8 . The compound of  claim 7 , wherein R 14  is an optionally substituted phenethyl. 
     
     
         9 . A presenter protein/compound complex comprising the compound of  claim 1  and a presenter protein. 
     
     
         10 . The complex of  claim 9 , wherein the presenter protein is FKBP12, FKBP12.6, FKBP25, or FKBP4. 
     
     
         11 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable excipient.