Proteasome inhibitors and uses thereof

Abstract

A method of treating a disease in which inhibiting of a proteasome is advantageous is provided. The method comprises administering to the subject a therapeutically effective amount of a compound which binds to a proteasome of a cell, the compound comprising a copper bound to a ligand, the ligand being configured such that upon binding to the proteasome, the copper interacts with cysteine 31 of a Beta2 subunit of the proteasome and further interacts with cysteine 118 of a Beta3 subunit of the proteasome, thereby treating the disease. Additional novel proteasome inhibitors are also provided as well as methods of identifying proteasome inhibitors.

What is claimed is: 
     
         1 . A method of treating a disease in which inhibiting of a proteasome is advantageous, the method comprising administering to the subject a therapeutically effective amount of a compound selected from the group consisting of NSC321206, NSC310551, NSC99671 and NSC3907, thereby treating the disease. 
     
     
         2 . A method of treating a disease in which inhibiting of a proteasome is advantageous, the method comprising administering to the subject a therapeutically effective amount of a compound which binds to a proteasome of a cell, said compound comprising a copper bound to a ligand, said ligand being configured such that upon binding to said proteasome, said copper interacts with cysteine 31 of a β2 subunit of said proteasome and further interacts with cysteine 118 of a β3 subunit of said proteasome, thereby treating the disease. 
     
     
         3 . The method of  claim 1 , wherein said disease is selected from the group consisting of cancer, an inflammatory disease and a neurodegenerative disease. 
     
     
         4 . The method of  claim 2 , wherein said disease is selected from the group consisting of cancer, an inflammatory disease and a neurodegenerative disease. 
     
     
         5 . An isolated polypeptide comprising a p53 amino acid sequence, having a different cellular location in a presence or absence or a proteasome inhibitor, the polypeptide being linked to a detectable moiety. 
     
     
         6 . The isolated polypeptide of  claim 5 , comprising an amino acid sequence as set forth by SEQ ID NO: 3. 
     
     
         7 . The isolated polypeptide of  claim 5 , comprising an amino acid sequence as set forth by SEQ ID NO: 6. 
     
     
         8 . The isolated polypeptide of  claim 5 , having a nuclear location in a presence of a proteasome inhibitor and a cytoplasmic location in an absence of a proteasome inhibitor. 
     
     
         9 . An isolated polynucleotide comprising a nucleic acid sequence encoding the polypeptide of  claim 5 . 
     
     
         10 . The isolated polynucleotide of  claim 9 , comprising a nucleic acid sequence as set forth in SEQ ID NO: 4. 
     
     
         11 . The isolated polynucleotide of  claim 9 , comprising a nucleic acid sequence as set forth in SEQ ID NO: 5. 
     
     
         12 . A cell population expressing the polypeptide of  claim 5 . 
     
     
         13 . The cell population of  claim 12  comprising H1299 non-small cell lung carcinoma cells. 
     
     
         14 . A method of identifying a proteasome inhibitor, the method comprising:
 (a) contacting a candidate inhibitor with a population of cells which express the isolated polypeptide of  claim 5 ; and   (b) analyzing a cellular location of said polypeptide in said population of cells, wherein a change in localization of said polypeptide is indicative of said candidate inhibitor being a proteasome inhibitor.   
     
     
         15 . A pharmaceutical composition comprising as an active ingredient a compound selected from the group consisting of NSC321206, NSC310551, NSC99671 and NSC3907 and a pharmaceutically acceptable carrier. 
     
     
         16 . A pharmaceutical composition comprising as an active ingredient a compound which binds to a proteasome of a cell, said compound comprising a copper bound to a ligand, said ligand being configured such that upon binding to said proteasome, said copper interacts with cysteine 31 of a β2 subunit of said proteasome and further interacts with cysteine 118 of a β3 subunit of said proteasome. 
     
     
         17 . A pharmaceutical composition comprising as an active ingredient a compound identified according to the method of  claim 14  and a pharmaceutically acceptable carrier.