Modified proteins and protein degraders

Abstract

Provided herein are compounds, pharmaceutical compositions, and methods for binding or degrading target proteins. Further provided herein are compounds having a DNA damage-binding protein 1 (DDB1) binding moiety. Some such embodiments include a linker. Some such embodiments include a target protein binding moiety. Further provided herein are ligand-DDB1 complexes. Further provided herein are in vivo modified DDB1 proteins.

1 . An in vivo modified protein comprising:
 a DNA damage-binding protein 1 (DDB1) protein comprising a beta propeller domain directly bound to a DDB1 ligand, wherein the DDB1 ligand comprises a non-peptide DDB1 binding moiety having a molecular weight below 2500 daltons.   
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . The in vivo modified protein of  claim 1 , wherein the beta propeller domain comprises a beta propeller C (BPC) domain. 
     
     
         6 . The in vivo modified protein of  claim 5 , wherein the DDB1 ligand is bound to a top face of the BPC domain. 
     
     
         7 . The in vivo modified protein of  claim 1 , wherein the DDB1 ligand is bound to one or more of the following DDB1 residues of the DDB1 protein: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, ALA834, VAL836, ALA841, ALA869, TYR871, SER872, MET910, LEU912, TYR913, LEU926, TRP953, SER955, ALA956, ASN970, ALA971, PHE972, PHE1003, ASN1005, VAL1006, or VAL1033. 
     
     
         8 . The in vivo modified protein of  claim 1 , wherein the binding between the beta propeller domain and the DDB1 ligand is non-covalent. 
     
     
         9 . (canceled) 
     
     
         10 . The in vivo modified protein of  claim 1 , wherein the binding between the DDB1 protein and the DDB1 ligand comprises a binding affinity with an equilibrium dissociation constant (Kd) below 100 μM. 
     
     
         11 . The in vivo modified protein of  claim 1 , wherein the binding between the DDB1 protein and the DDB1 ligand comprises a binding affinity with a Kd below 20 μM. 
     
     
         12 . The in vivo modified protein of  claim 1 , wherein the DDB1 ligand comprises a small molecule. 
     
     
         13 . (canceled) 
     
     
         14 . The in vivo modified protein of  claim 1 , wherein the DDB1 ligand is synthetic. 
     
     
         15 . The in vivo modified protein of  claim 1 , wherein the DDB1 binding moiety comprises the structure of any one of compounds B-1 to B-176, or a salt thereof. 
     
     
         16 . (canceled) 
     
     
         17 . The in vivo modified protein of  claim 1 , wherein the DDB1 ligand further comprises a target protein binding moiety covalently connected by a linker to the DDB1 binding moiety. 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . The in vivo modified protein of  claim 17 , wherein the target protein binding moiety binds to a target protein in a cell, and wherein binding of the DDB1 ligand to the target protein results in degradation of the target protein in the cell. 
     
     
         21 . (canceled) 
     
     
         22 . The in vivo modified protein of  claim 1 , wherein the DDB1 ligand is a heterobifunctional compound comprising the structure of Formula (IIc): 
       
         
           
           
               
               
           
         
         wherein 
         F 2  is aryl, heteroaryl, carbocyclyl, or heterocyclyl; 
         L 2  is a bond, —C(═O)NR 13 —, —NR 13 C(═O)—, —C(═O)—, —C(═S)—, —S—, —S(═O), —S(═O) 2 —, —S(═O)NR 13 —, —NR 13 S(═O)—, —S(═O) 2 NR 13 —, —NR 13 S(═O) 2 —, —O—, C 1 -C 4  alkyl, or C 1 -C 4  haloalkyl, C 1 -C 4  heteroalkyl, C 1 -C 4  alkoxy, C 1 -C 4  alkylamino, C 1 -C 4  alkenyl, or C 1 -C 4  alkynyl, wherein each R 13  is independently hydrogen, —S(═O)R b , —S(═O) 2 R d , —S(═O) 2 NR c R d , —C(═O)R b , —CO 2 R a , —C(═O)NR c R d , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  heteroalkyl, C 3 -C 8  carbocyclyl, C 2 -C 8  heterocyclyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OR a , or —NR c R d ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —OR a , or —NR c R d ; 
         each R 11  and R 12  is independently hydrogen, halogen, —CN, —R a , —OR a , —SR a , —S(═O)R b , —NO 2 , —NR c R d , —S(═O) 2 R d , —NR a S(═O) 2 R d , —S(═O) 2 NR c R d , —C(═O)R b , —OC(═O)R b , —CO 2 R a , —OCO 2 R a , —C(═O)NR c R d , —OC(═O)NR c R d , —NR a C(═O)NR c R d , —NR a C(═O)R b , —NR a C(═O)OR a , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  heteroalkyl, C 3 -C 8  carbocyclyl, C 2 -C 8  heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —R a , —OR a , or NR c R d ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —R a , —OR a , or —NR c R d ; 
         each R a  is independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  heteroalkyl, C 3 -C 8  carbocyclyl, C 2 -C 8  heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OH, —OMe, or —NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —OH, —OMe, or —NH 2 ; 
         each R b  is independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  heteroalkyl, C 3 -C 8  carbocyclyl, C 2 -C 8  heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OH, —OMe, or —NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —OH, —OMe, or —NH 2 ; 
         each R c  and R d  is independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  heteroalkyl, C 3 -C 8  carbocyclyl, C 2 -C 8  heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OH, —OMe, or —NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —OH, —OMe, or —NH 2 , 
         each R c  and R d , together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —OH, —OMe, or —NH 2 ; 
         q is 1-4; 
         s is 1-5; 
         L 1  is a linker; and 
         Z 1  is a target protein binding moiety. 
       
     
     
         23 . The in vivo modified protein of  claim 1 , wherein the DDB1 ligand is a heterobifunctional compound comprising the structure of Formula (IId): 
       
         
           
           
               
               
           
         
       
       wherein
 F 2  is aryl, heteroaryl, carbocyclyl, or heterocyclyl; 
 L 2  is a bond, —C(═O)NR 13 —, —NR 13 C(═O)—, —C(═O)—, —C(═S)—, —S—, —S(═O), —S(═O) 2 —, —S(═O)NR 13 —, —NR 13 S(═O)—, —S(═O) 2 NR 13 —, —NR 13 S(═O) 2 —, —O—, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 1 -C 4  heteroalkyl, C 1 -C 4  alkoxy, C 1 -C 4  alkylamino, C 1 -C 4  alkenyl, or C 1 -C4 alkynyl, wherein each R 13  is independently hydrogen, —S(═O)R b , —S(═O) 2 R d , —S(═O) 2 NR c R d , —C(═O)R d , —CO 2 R a , —C(═O)NR c R d , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  heteroalkyl, C 3 -C 8  carbocyclyl, C 2 -C 8  heterocyclyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OR a , or —NR c R d ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —OR a , or —NR c R d ; 
 each R 11  and R 12  is independently hydrogen, halogen, —CN, —R a , —OR a , —SR a , —S(═O)R b , —NO 2 , —NR c R d , —S(═O) 2 R d , —NR a S(═O) 2 R d , —S(═O) 2 NR c R d , —C(═O)R b , —OC(═O)R b , —CO 2 R a , —OCO 2 R a , —C(═O)NR c R d , —OC(═O)NR c R d , —NR a C(═O)NR c R d , —NR a C(═O)R b , —NR a C(═O)OR a , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  heteroalkyl, C 3 -C 8  carbocyclyl, C 2 -C 8  heterocyclyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —R a , —OR a , or NR c R d ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —R a , —OR a , or —NR c R d ; 
 each R a  is independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  heteroalkyl, C 3 -C 8  carbocyclyl, C 2 -C 8  heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OH, —OMe, or —NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —OH, —OMe, or —NH 2 ; 
 each R b  is independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  heteroalkyl, C 3 -C 8  carbocyclyl, C 2 -C 8  heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OH, —OMe, or —NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —OH, —OMe, or —NH 2 ; 
 each R c  and R d  is independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  heteroalkyl, C 3 -C 8  carbocyclyl, C 2 -C 8  heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OH, —OMe, or —NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —OH, —OMe, or —NH 2 ; 
 each R c  and R d , together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —OH, —OMe, or —NH 2 ; 
 q is 1-4; 
 s is 1-5; 
 L 1  is a linker; and 
 Z is a target protein binding moiety. 
 
     
     
         24 . The in vivo modified protein of  claim 1 , wherein the DDB1 ligand is a heterobifunctional compound comprising the structure of Formula (IIe): 
       
         
           
           
               
               
           
         
       
       wherein
 F 2  is aryl, heteroaryl, carbocyclyl, or heterocyclyl; 
 L 2  is a bond, —C(═O)NR 13 —, —NR 13 C(═O)—, —C(═O)—, —C(═S)—, —S—, —S(═O), —S(═O) 2 —, —S(═O)NR 13 —, —NR 13 S(═O)—, —S(═O) 2 NR 13 —, —NR 13 S(═O) 2 —, —O—, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 1 -C 4  heteroalkyl, C 1 -C 4  alkoxy, C 1 -C 4  alkylamino, C 1 -C 4  alkenyl, or C 1 -C 4  alkynyl, wherein each R 13  is independently hydrogen, —S(═O)R b , —S(═O) 2 R d , —S(═O) 2 NR c R d , —C(═O)R b , —CO 2 R a , —C(═O)NR c R d , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  heteroalkyl, C 3 -C 8  carbocyclyl, C 2 -C 8  heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OR a , or —NR c R d ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —OR a , or —NR c R d ; 
 each R 11  and R 12  is independently hydrogen, halogen, —CN, —R a , —OR a , —SR a , —S(═O)R b , —NO 2 , —NR c R d , —S(═O) 2 R d , —NR a S(═O) 2 R d , —S(═O) 2 NR c R d , —C(═O)R b , —OC(═O)R b , —CO 2 R a , —OCO 2 R a , —C(═O)NR c R d , —OC(═O)NR c R d , —NR a C(═O)NR c R d , —NR a C(═O)R b , —NR a C(═O)OR a , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  heteroalkyl, C 3 -C 8  carbocyclyl, C 2 -C 8  heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —R a , —OR a , or NR c R d ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —R a , —OR a , or —NR c R d ; 
 each R a  is independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  heteroalkyl, C 3 -C 8  carbocyclyl, C 2 -C 8  heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OH, —OMe, or —NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —OH, —OMe, or —NH 2 ; 
 each R b  is independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  heteroalkyl, C 3 -C 8  carbocyclyl, C 2 -C 8  heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OH, —OMe, or —NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —OH, —OMe, or —NH 2 ; 
 each R c  and R d  is independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  heteroalkyl, C 3 -C 8  carbocyclyl, C 2 -C 8  heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OH, —OMe, or —NH 2 ; and the carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —OH, —OMe, or —NH 2 ; 
 each R c  and R d , together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl; wherein the heterocyclyl and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —OH, —OMe, or —NH 2 ; 
 q is 1-4; 
 s is 1-5; 
 L 1  is a linker; and 
 Z 1  is a target protein binding moiety. 
 
     
     
         25 . The in vivo modified protein of  claim 22 , wherein F 2  is aryl. 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . The in vivo modified protein of  claim 25 , wherein F 2  is 5-12 membered heteroaryl. 
     
     
         29 . The in vivo modified protein of  claim 22 , wherein L 2  is —C(═O)NH— or —C(═O)N(C 1 -C 5  alkyl)-. 
     
     
         30 . (canceled) 
     
     
         31 . The in vivo modified protein of  claim 22 , wherein q is 1 or 2. 
     
     
         32 . (canceled) 
     
     
         33 . The in vivo modified protein of  claim 22 , wherein the linker comprises —(CH 2 ) p2 NH(CH 2 ) p1 NH—, —(CH 2 ) p2 NH(CH 2 ) p1 C(═O)NH—, —(CH 2 ) p2 NH(CH 2 ) p1 NHC(═O)—, —(CH 2 ) p2 NH(CH 2 CH 2 )(OCH 2 CH 2 ) p1 NH—, —(CH 2 ) p2 NH(CH 2 CH 2 )(OCH 2 CH 2 ) p1 C(═O)NH—, or —(CH 2 ) p2 NH(CH 2 CH 2 )(OCH 2 CH 2 ) p1 NHC(═O)—, wherein p1 is 1-15, and p2 is 0-15.