Small Molecule Inhibitors Selective For Polo-Like Kinase Proteins

Abstract

Disclosed are small molecule PLK inhibitors that can target the polo box domain (PBD). Inhibitors can have an atomic mass of about 1000 Da or less and a general structure of For instance, the inhibitors can include an alkyl benzamido benzoic acid core structure.

What is claimed is: 
     
         1 . A small molecule PLK inhibitor having the general structure: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  comprises an alkyl, —O-alkyl, —S-alkyl, or —NH-alkyl, and optionally includes a terminal aryl; 
 R 8  and R 9  are independently hydrogen, alkyl, OH, NH 2 , SH, —S-alkyl, —O-alkyl, —NH-alkyl, —CONH-alkyl, halogen, or —CN; 
 X is an amide, —C1 to C4 alkyl-NH—, —NH—, —SNH—, —SONH—, or —SO 2 N—; 
 R 7  is selected from the following structures: 
 
       
         
           
           
               
               
           
         
         in which
 R 2  through R 6  are independently selected from hydrogen, carboxyl, alkyl, alkyl ester, hydroxyl, methoxy, halogen, sulfonamide, phosphate, nitro, methylamine, or boronic acid, and 
 R 10  is C or N, and R 3  is relevant only when R 10  is C; 
 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The small molecule PLK inhibitor of  claim 1 , wherein the small molecule inhibitor is selective for PLK1. 
     
     
         3 . The small molecule PLK inhibitor of  claim 1 , wherein R 1  is a C3 to C8 alkyl group, R 8  and R 9  are hydrogen, R 7  is a), R 2  is carboxyl, R 3  through R 6  are independently selected from hydrogen, hydroxyl, methoxy, halogen, nitro, or alkyl, R 10  is C, and X is an amide linkage. 
     
     
         4 . The small molecule PLK inhibitor of  claim 1 , wherein at least one of R 2  through R 6  is a C3 to C8 alkyl group. 
     
     
         5 . The small molecule PLK inhibitor of  claim 4 , wherein R 4  is a methyl group. 
     
     
         6 . The small molecule PLK inhibitor of  claim 1 , wherein the small molecule inhibitor is selective for PLK3. 
     
     
         7 . The small molecule PLK inhibitor of  claim 6 , wherein R 1  comprises a C6 to C12 alkyl, R 8  and R 9  are hydrogen, R 7  is a), R 2  is hydrogen or carboxyl, R 3  through R 6  are independently selected from hydrogen, carboxyl, methyl, or hydroxyl, R 10  is C, and X an amide linkage. 
     
     
         8 . The small molecule PLK inhibitor of  claim 7 , wherein R 1  comprises a C10 to C12 alkyl. 
     
     
         9 . The small molecule PLK inhibitor of  claim 1 , wherein the inhibitor has an atomic mass of about 1000 Daltons or less. 
     
     
         10 . The small molecule PLK inhibitor of  claim 1 , wherein the inhibitor has an atomic mass of about 500 Daltons or less. 
     
     
         11 . The small molecule PLK inhibitor of  claim 1 , wherein the inhibitor has a polar surface area of about 200 Å or less. 
     
     
         12 . The small molecule PLK inhibitor of  claim 1 , wherein the inhibitor has a polar surface area of about 100 Å or less. 
     
     
         13 . The small molecule PLK inhibitor of  claim 1 , wherein the inhibitor induces apoptosis. 
     
     
         14 . The small molecule PLK inhibitor of  claim 1 , wherein the inhibitor has the following structure: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  comprises an alkyl, —O-alkyl, —S-alkyl, or —NH-alkyl, and optionally includes a terminal aryl; 
 R 2  through R 6  are independently selected from hydrogen, carboxyl, alkyl, alkyl ester, hydroxyl, methoxy, halogen, sulfonamide, phosphate, nitro, methylamine or boronic acid; and 
 X is an amide, —C1 to C4 alkyl-NH—, —NH—, —SNH—, —SONH—, or —SO 2 N—. 
 
     
     
         15 . The small molecule PLK inhibitor of  claim 14 , wherein R 1  is C3 to C8 alkyl and X is an amide. 
     
     
         16 . The small molecule PLK inhibitor of  claim 1 , wherein the inhibitor has the following structure: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  comprises an alkyl, —O-alkyl, —S-alkyl, or —NH-alkyl, and optionally includes a terminal aryl; 
 R 7  is selected from: