Small Molecule Drug Conjugates

Abstract

A binding moiety (B) for Carbonic Anhydrase IX (CAIX), the binding moiety comprising: The binding moiety is univalent, bivalent, or multivalent. A targeted therapeutic agent may comprise the binding moiety. The invention also includes a method for treating a disease expressing elevated levels of CAIX by administering the targeted therapeutic agent.

1 . A targeted therapeutic agent comprising a compound of formula:
   B-L-D  (I),
   wherein:
 B is a low molecular weight binding moiety for Carbonic Anhydrase IX (CAIX); 
 D is a drug moiety; 
 L is a linker that undergoes cleavage in vivo for releasing said drug moiety in an active form;
 wherein said linker comprises a polar or charged moiety for improving water solubility of said compound; and
 wherein said polar or charged moiety is an oligomer comprising from 1 to about 20 monomers selected from the group consisting of natural and non-natural amino acids, saccharides, (meth)acrylic acid and salts thereof, hydroxyethyl (meth)acrylate, and ethylene glycol. 
 
 
   
     
     
         2 . The targeted therapeutic agent of  claim 1 , wherein said linker group comprises a 1,2,3-triazole ring, wherein said drug moiety and binding moiety are linked to positions 1 and 4 of said triazole ring, and wherein position 5 of the triazole ring is optionally substituted. 
     
     
         3 . The targeted therapeutic agent of  claim 1 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
         wherein:
 Hy is a hydrophilic moiety for improving the solubility of the conjugate; 
 S—S represents a cleavable disulfide bond between the drug moiety and the linker; 
 Sp are spacer groups, independently selected from the group consisting of one or more optionally substituted straight or branched or cyclic C1-C6 alkylene, optionally substituted straight or branched or cyclic C1-C6 alkenylene, carbonyl carbons, ether, thioether O or S atoms, and amine N atoms; and 
 R is selected from the group consisting of H, halogen, carboxylate, substituted or unsubstituted (hetero)alkyl, (hetero)alkenyl, (hetero)alkynyl, (hetero)aryl, (hetero)arylalkyl, (hetero)cycloalkyl, (hetero)cycloalkylaryl, heterocyclylalkyl, a peptide, an oligosaccharide, and a steroid group. 
 
       
     
     
         4 . The targeted therapeutic agent of  claim 1 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The targeted therapeutic agent of  claim 1 , wherein said binding moiety is a multivalent binding moiety having two or more ligands for binding to CAIX. 
     
     
         6 . The targeted therapeutic agent of  claim 5 , wherein a terminal moiety of at least one of said two or more binding ligands is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         7 . The targeted therapeutic agent of  claim 6 , wherein said binding moiety is a bivalent binding moiety comprising a first binding ligand and a second binding ligand,
 wherein said first binding ligand comprises said terminal moiety of  claim 6 ; and   wherein said second binding ligand is selected from the group consisting of ligands having said terminal moiety of  claim 6  and ligands having terminal group   
       
         
           
           
               
               
           
         
         
           wherein R′ is selected from the group consisting of H, optionally substituted C1-C7 alkyl, optionally substituted C1-C7 alkenyl, and optionally substituted C1-C7 heteroalkyl. 
         
       
     
     
         8 . The targeted therapeutic agent of  claim 5 , wherein said compound has formula B7 of  FIG. 11 . 
     
     
         9 . The targeted therapeutic agent of  claim 5 , wherein the binding moiety comprises: 
       
         
           
           
               
               
           
         
         wherein R is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         wherein R′ is selected from the group consisting of H, optionally substituted C1-C7 alkyl, optionally substituted C1-C7 alkenyl, and optionally substituted C1-C7 heteroalkyl. 
       
     
     
         10 . The targeted therapeutic agent of  claim 1 , wherein the linker comprises a peptide that is cleavable by a protease that is present in the extracellular matrix of a tumor or that is released after tumor cell death. 
     
     
         11 . The targeted therapeutic agent of  claim 10  wherein said protease is selected from the group consisting of MMP-1, MMP-2, MMP-3, Cathepsin A, Cathepsin B, and Cathepsin C. 
     
     
         12 . The targeted therapeutic agent of  claim 10 , wherein the linker comprises valine-citrulline and is cleavable by Cathepsin B. 
     
     
         13 . The targeted therapeutic agent of  claim 10 , wherein the linker further comprises a self-immolating spacer. 
     
     
         14 . The targeted therapeutic agent of  claim 10 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The targeted therapeutic agent of  claim 1 , wherein the linker contains a glucuronide moiety that is cleavable by glucuronidases. 
     
     
         17 . A combined preparation comprising the compound of  claim 1  and an antibody-drug conjugate (ADC) and a cleavage agent for cleaving said cleavable linker. 
     
     
         18 . The combined preparation of  claim 17 , wherein either: (a) said linker comprises a disulphide bond and the cleavage agent comprises a reducing agent selected from the group consisting of cysteine, N-acetylcysteine, and ordithiothreitol; or (b) said linker comprises an amide linkage and said cleavage agent comprises a hydrolase; or (c) said linker comprises an ester linkage and said cleavage agent comprises a hydrolase. 
     
     
         19 . A targeted therapeutic agent comprising a compound of formula:
   B-L-D  (I),
   wherein:
 B is a low molecular weight binding moiety for Carbonic Anhydrase IX (CAIX); 
 D is a drug moiety; 
 L is a linker that undergoes cleavage in vivo for releasing said drug moiety in an active form;
 wherein said binding moiety is a multivalent binding moiety having two or more ligands for binding to CAIX. 
 
   
     
     
         20 . The targeted therapeutic agent of  claim 19 , wherein a terminal moiety of at least one of said two or more binding ligands is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         21 . The targeted therapeutic agent of  claim 20 , wherein said binding moiety is a bivalent binding moiety comprising a first binding ligand and a second binding ligand,
 wherein said first binding ligand comprises said terminal moiety of  claim 20 ; and   wherein said second binding ligand is selected from the group consisting of ligands having said terminal moiety of  claim 20  and ligands having terminal group   
       
         
           
           
               
               
           
         
         
           wherein R′ is selected from the group consisting of H, optionally substituted C1-C7 alkyl, optionally substituted C1-C7 alkenyl, and optionally substituted C1-C7 heteroalkyl. 
         
       
     
     
         23 . The targeted therapeutic agent of  claim 19 , wherein the binding moiety comprises: 
       
         
           
           
               
               
           
         
         wherein R is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         wherein R′ is selected from the group consisting of H, optionally substituted C1-C7 alkyl, optionally substituted C1-C7 alkenyl, and optionally substituted C1-C7 heteroalkyl. 
       
     
     
         24 . The targeted therapeutic agent of  claim 19 , wherein the linker comprises a peptide that is cleavable by a protease that is present in the extracellular matrix of a tumor or that is released after tumor cell death. 
     
     
         25 . The targeted therapeutic agent of  claim 24  wherein said protease is selected from the group consisting of MMP-1, MMP-2, MMP-3, Cathepsin A, Cathepsin B, and Cathepsin C. 
     
     
         26 . The targeted therapeutic agent of  claim 24 , wherein the linker comprises valine-citrulline and is cleavable by Cathepsin B. 
     
     
         27 . The targeted therapeutic agent of  claim 24 , wherein the linker further comprises a self-immolating spacer. 
     
     
         28 . The targeted therapeutic agent of  claim 24 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         29 . The targeted therapeutic agent of  claim 19 , wherein the linker contains a glucuronide moiety that is cleavable by glucuronidases. 
     
     
         31 . A combined preparation comprising the compound of  claim 19  and an antibody-drug conjugate (ADC) and a cleavage agent for cleaving said cleavable linker. 
     
     
         32 . The combined preparation of  claim 19 , wherein either: (a) said linker comprises a disulphide bond and the cleavage agent comprises a reducing agent selected from the group consisting of cysteine, N-acetylcysteine, and ordithiothreitol; or (b) said linker comprises an amide linkage and said cleavage agent comprises a hydrolase; or (c) said linker comprises an ester linkage and said cleavage agent comprises a hydrolase.