Methods of Blocking the CXCR-4/SDF-1 Signaling Pathway With Inhibitors of Bruton's Tyrosine Kinase

Abstract

In some embodiments, the present invention relates to novel small molecule inhibitors that block the CXCR4-SDF-1 signaling pathway by directly inhibiting members of the Tec family of kinases, namely Bruton's tyrosine kinase (BTK), and their use in treating diseases in which pathogenesis is mediated by the CXCR4/SDF-1 signaling pathway.

1 . A method of treating a disorder associated with overexpression of CXCR4 and/or dysregulated signaling of CXCR4, comprising administering to a patient having the disorder an effective amount of a BTK inhibitor or a pharmaceutically acceptable salt, hydrate, or solvate thereof to effectively block the CXCR4/SDF-1 pathway. 
     
     
         2 . The method of  claim 1 , wherein the BTK inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt, solvate, or hydrate thereof. 
     
     
         3 . The method of  claim 2 , wherein the disorder is selected from the group consisting of osteosarcoma, sarcoma, glioblastoma multiforme, rheumatoid arthritis, lupus, IgA nephropathy, membranous nephropathy, and pemphigus. 
     
     
         4 . A pharmaceutical composition comprising a BTK inhibitor, or a pharmaceutically acceptable salt, solvate, or hydrate thereof for use in treating a disorder associated with overexpression of CXCR4 or dysregulated signaling of CXCR4, and pharmaceutically acceptable carrier, diluent, or excipient. 
     
     
         5 . The pharmaceutical composition of  claim 4 , wherein the BTK inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt, solvate, or hydrate thereof. 
     
     
         6 . A method of blocking CXCR4/SDF-1 signaling in a subject in need thereof, comprising administering to the subject an effective amount of a BTK inhibitor or a pharmaceutically acceptable salt, solvate, or hydrate thereof to effectively block the CXCR4/SDF-1 pathway. 
     
     
         7 . The method of  claim 6 , wherein the BTK inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt, solvate, or hydrate thereof. 
     
     
         8 . (canceled)