Methods of treating autoimmune and/or glomerulonephritis-associated diseases using shp2 inhibitors

Abstract

Methods are disclosed herein for administering a oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) inhibitor for treating autoimmune and/or glomerulonephritis-associated diseases, and in particular, Systemic Lupus Erythematosus (SLE).

What is claimed is: 
     
         1 . A method for inhibiting specific oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) phosphatase activity, the method comprising administering to a subject in need thereof a specific oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) inhibitor having the formula (I): 
       
         
           
           
               
               
           
         
       
       wherein R 1 =NRaRb, wherein Ra or Rb can each independently be selected from the group consisting of hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted fused 5-12 member aromatic or aliphatic ring system, wherein the substitution on the fused 5-12 member aromatic or aliphatic ring system is selected from the group consisting of nitrogen, oxygen and sulfur. 
     
     
         2 . The method of  claim 1  wherein the SHP2 inhibitor has the formula selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . The method of  claim 1  wherein the SHP2 inhibitor is administered using an administration route selected from the group consisting of: oral (po), intravenous (iv), intramuscular (im), subcutaneous (sc), parenteral, transdermal, inhalation, buccal, ocular, sublingual, vaginal, rectal, and combinations thereof. 
     
     
         4 . The method of  claim 1  wherein the SHP2 inhibitor is administered in an amount ranging from about 1 mg/Kg body weight/day to about 25 mg/Kg body weight/day. 
     
     
         5 . The method of  claim 1  wherein the SHP2 inhibitor is administered in an amount ranging from about 5 mg/Kg body weight/day to about 10 mg/Kg body weight/day. 
     
     
         6 . The method of  claim 1  wherein the SHP2 inhibitor is administered in an amount of about 7.5 mg/Kg body weight/day. 
     
     
         7 . A method for treating glomerulonephritis-associated diseases in a subject in need thereof, the method comprising administering to the subject a specific oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) inhibitor. 
     
     
         8 . The method of  claim 7  wherein the SHP2 inhibitor has the formula (I): 
       
         
           
           
               
               
           
         
       
       wherein R 1 =NRaRb, wherein Ra or Rb can each independently be selected from the group consisting of hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted fused 5-12 member aromatic or aliphatic ring system, wherein the substitution on the fused 5-12 member aromatic or aliphatic ring system is selected from the group consisting of nitrogen, oxygen and sulfur. 
     
     
         9 . The method of  claim 8  wherein the SHP2 inhibitor has the formula selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         10 . The method of  claim 9  wherein the SHP2 inhibitor has an IC 50  value of less than 1 μM. 
     
     
         11 . The method of  claim 7  wherein the glomerulonephritis-associated disease is selected from the group consisting of postinfectious rapidly progressive glomerulonephritis (RPGN), idiopathic rapidly progressive glomerulonephritis (RPGN), systemic lupus erythematosus (SLE), Goodpasture's syndrome, vasculitis, Wegener's granulomatosis, Henoch-Schonlein purpura, essential cryoglobulinemia, acute proliferative glomerulonephritis, microscopic polyangiitis, Churg-Stauss Syndrome, and IgA neuropathy. 
     
     
         12 . The method of  claim 7  wherein the SHP2 inhibitor is administered in an amount ranging from about 1 mg/Kg body weight/day to about 25 mg/Kg body weight/day. 
     
     
         13 . The method of  claim 7  wherein the SHP2 inhibitor is administered in an amount ranging from about 5 mg/Kg body weight/day to about 10 mg/Kg body weight/day. 
     
     
         14 . The method of  claim 7  wherein the SHP2 inhibitor is administered in an amount of about 7.5 mg/Kg body weight/day.