Peptides and chemical compound for inhibition of SHP2 function

Abstract

The present invention relates to the inhibition of the function of SHP2 by both anti-SHP2 peptides and the chemical compound 4-(2-sulfaminoethyl)benzoic acid, SEBA, and SEBA derivatives binding to the phosphotyrosyl phosphatase domain of SHP2 thereby inhibiting the function of SHP2 both in vitro and in vivo. In addition, the inhibition of SHP2 may be useful as a treatment for human disease, and it has been shown that interfering with SHP2 function using the anti-SHP2 peptides and SEBA compounds reverses cell transformation and induces remission of preformed tumors in vivo demonstrating a possible treatment for cancer.

1 . A SEBA derivative comprised of the structure 
       
         
           
           
               
               
           
         
         wherein R′ is selected from the functional group consisting of the amino acids sequence D-V; D-G; D-A; D-G-D-G; D-A-D-A; D-V-D-V; D-A-D-V; D-A-D-G; D-G-D-V; D-G-D-A; D-V-D-G; and D-V-D-A, and R is selected from the functional groups acetate, phosphate, sulfate, and aminosulfate. 
       
     
     
         2 . A method to inhibit SHP2 function comprising a blocker preventing the binding of biological substrates to the active site of the phosphotyrosyl phosphatase domain of SHP2 wherein said blocker is a SEBA derivative comprising of 
       
         
           
           
               
               
           
         
         wherein R′ is selected from the functional group consisting of the amino acids sequence D-V; D-G; D-A; D-G-D-G; D-A-D-A; D-V-D-V; D-A-D-V; D-A-D-G; D-G-D-V; D-G-D-A; D-V-D-G; and D-V-D-A, and R is selected from the functional groups acetate; 
         phosphate, sulfate, and aminosulfate binding to said site. 
       
     
     
         3 . The method to inhibit SHP2 function of  claim 2  wherein an effective amount of said chemical compound is used in the treatment of a human disease. 
     
     
         4 . The method to inhibit SHP2 function of  claim 3  wherein said human disease is cancer. 
     
     
         5 . A chemical compound SEBA comprising 4-(2-sulfaminoethyl)benzoic acid. 
     
     
         6 . The chemical compound SEBA of  claim 5  wherein an effective amount of said SEBA inhibits the function of SHP2 by binding to the active site of the phosphotyrosyl phosphatase domain of said SHP2. 
     
     
         7 . The chemical compound SEBA of  claim 6  wherein an effective amount of said SEBA is used in the treatment of a human disease. 
     
     
         8 . The chemical compound SEBA of  claim 7  wherein said human disease is cancer.