Proteolysis Targeting Chimera Compounds and Methods of Preparing and Using Same

Abstract

The present invention includes novel compounds and methods for preventing or treating diseases associated with and/or caused by overexpression and/or uncontrolled activation of a tyrosine kinase in a subject in need thereof. In certain embodiments, the compounds of the present invention comprise a tyrosine kinase inhibitor, a linker and a ubiquitin ligase binder. The methods of the present invention comprise administering to the subject an pharmaceutically effective amount of at least one compound of the invention.

1 - 20 . (canceled) 
     
     
         21 . A method of treating or preventing a disease or disorder associated with overexpression and/or uncontrolled activation of c-Abl and/or BCR-ABL, the method comprising administering to the subject a therapeutically effective amount of at least one compound of formula (I):
   TKI-L-(ULM) k   (I),
   
       wherein:
 TKI is a tyrosine kinase inhibitor, 
 L is a linker, 
 each ULM is independently a ubiquitin ligase binder, and 
 k is an integer ranging from 1 to 4, 
 
       wherein TKI is covalently linked to L and wherein each ULM is covalently linked to L, 
       wherein TKI is capable of binding to c-ABL and/or BCR-ABL or a salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof. 
     
     
         22 . The method of  claim 21 , wherein the disease or disorder comprises cancer. 
     
     
         23 . The method of  claim 22 , wherein the cancer comprises chronic myelogenous leukemia (CML). 
     
     
         24 . The method of  claim 21 , wherein the compound is administered to the subject by at least one route selected from the group consisting of nasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intrathecal and intravenous routes. 
     
     
         25 . A method of preventing or treating a tyrosine kinase-dependent cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one compound of formula (I).
   TKI-L-(ULM) k   (I),
   
       wherein:
 TKI is a tyrosine kinase inhibitor, 
 L is a linker, 
 each ULM is independently a ubiquitin ligase binder, and 
 k is an integer ranging from 1 to 4, 
 
       wherein TKI is covalently linked to L and wherein each ULM is covalently linked to L, or a salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof. 
     
     
         26 . The compound of  claim 25 , wherein TKI is capable of binding to c-ABL and/or BCR-ABL. 
     
     
         27 . The method of  claim 25 , wherein the cancer is associated with overexpression and/or uncontrolled activation of the tyrosine kinase. 
     
     
         28 . The method of  claim 25 , wherein the tyrosine kinase is oncogenic. 
     
     
         29 . The method of  claim 25 , wherein the subject is a human. 
     
     
         30 . The method of  claim 25 , wherein the cancer comprises chronic myelogenous leukemia. 
     
     
         31 . The method of  claim 25 , wherein the compound is administered to the subject by at least one route selected from the group consisting of nasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intrathecal and intravenous routes.