Sigma-2 receptor ligand drug conjugates as antitumor compounds, methods of synthesis and uses thereof

Abstract

Methods and compositions for treating cancers such as pancreatic cancer and synovial sarcoma are disclosed. Compounds comprising a sigma-2 receptor-binding moiety and a ferroptosis-inducing moiety are described. At least one described molecular species exhibits an IC 50 value below 5 μM against human pancreatic cancer cells in vitro. Administration of this species promoted shrinkage of pancreatic cancer tumors in a murine model system in vivo, and led to 100% survival of experimental animals over a time course in which control therapies provided only 30% or 40% survival. Methods of synthesis of molecular species are also disclosed.

1 . A compound or a salt thereof, of structure 
       
         
           
           
               
               
           
         
         Wherein n is an integer from 1 to 5 and R 1  is H or methyl. 
       
     
     
         2 . A compound of salt thereof in accordance with  claim 1 , wherein n=1 and R 1 ═H. 
     
     
         3 . A compound or salt thereof in accordance with  claim 1 , wherein n=5 and R 1 ═H. 
     
     
         4 . A compound or salt thereof in accordance with any one of  claims 1 - 3 , wherein the salt is an oxalate salt. 
     
     
         5 . A method of treating a cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or salt thereof of any one of  claims 1 - 3 . 
     
     
         6 . A method of treating a cancer in accordance with  claim 5 , wherein the compound or salt thereof is the compound of salt thereof of  claim 2 . 
     
     
         7 . A method of treating a cancer in accordance with  claim 5 , wherein the compound or salt thereof is the compound of salt thereof of  claim 3 . 
     
     
         8 . A method of treating a cancer in accordance with any one of  claims 5 - 7 , wherein the cancer is a pancreatic cancer. 
     
     
         9 . A method of treating a cancer in accordance with any one of  claims 5 - 7 , wherein the cancer is a synovial sarcoma. 
     
     
         10 . A method of synthesizing a compound of  claim 1 , comprising reacting a compound of 
       
         
           
           
               
               
           
         
       
       with a compound of structure 
       
         
           
           
               
               
           
         
       
       wherein n is an integer from 1 to 5 and R 1  is methyl or H 
     
     
         11 . A method in accordance with  claim 10 , wherein n=1 and R1═H. 
     
     
         12 . A method in accordance with  claim 10 , wherein n=5 and R1═H. 
     
     
         13 . A compound or salt thereof of  claim 1  for use in the treatment of a cancer. 
     
     
         14 . A compound or salt thereof of  claim 13 , wherein the cancer is pancreatic cancer. 
     
     
         15 . A compound or salt thereof of  claim 13 , wherein the cancer is synovial sarcoma. 
     
     
         16 . Use of a compound or salt thereof of  claim 1  for the manufacture of a medicament for the treatment of cancer. 
     
     
         17 . Use of a compound or salt thereof in accordance with  claim 16 , wherein the cancer is a pancreatic cancer. 
     
     
         18 . Use of a compound or salt thereof in accordance with  claim 16 , wherein the cancer is a synovial sarcoma.