US2023364178A1PendingUtilityA1

Small Molecule Cancer Treatments that Cause Necrosis in Cancer Cells But Do Not Affect Normal Cells

Assignee: UNIV NEW YORK STATE RES FOUNDPriority: Nov 26, 2007Filed: Sep 27, 2022Published: Nov 16, 2023
Est. expiryNov 26, 2027(~1.3 yrs left)· nominal 20-yr term from priority
A61K 38/03A61K 31/155A61K 31/4995A61K 38/10A61K 38/1709A61K 38/1758C07K 14/4746A61K 47/54A61K 45/06C07K 2319/03A61P 35/00
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Claims

Abstract

A method of treating cancer in a subject, including: providing a subject having a plurality of cancer cells; and administering to the subject, a therapeutically effective amount of a composition including: an HDM-2 binding component; and a membrane resident component, the membrane resident component bound to the HDM-2 binding component. Also provided are a method of selectively necrosing cancer cells, a method of causing membranolysis in cancer cells, and a cancer treatment composition.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A method of treating cancer in a subject, said method comprising:
 providing a subject having a plurality of cancer cells; and   administering to the subject, a therapeutically effective amount of a composition including:
 an HDM-2 binding component selected from the group consisting of: 
   
       
         
           
                 
                 
                 
               
                     
                     
                   12-26 p53 protein, residues 
                 
                 
                 
               
                     
                   (SEQ ID NO: 1) 
                 
                 
                 
                 
               
                     
                     
                   (PPLSQETFSDLWKLL), 
                 
                     
                     
                 
                     
                     
                   17-26 p53 protein, residues 
                 
                 
                 
               
                     
                   (SEQ ID NO: 2) 
                 
                 
                 
                 
               
                     
                     
                   (ETFSDLWKLL), 
                 
                     
                     
                 
                     
                     
                   12-26 p53 protein, residues 
                 
                 
                 
               
                     
                   (SEQ ID NO: 1) 
                 
                 
                 
                 
               
                     
                     
                   (P*P*LSQETFSDLWKLL), 
                 
                     
                     
                 
                     
                     
                   17-26 p53 protein, residues 
                 
                 
                 
               
                     
                   (SEQ ID NO: 2) 
                 
                 
                 
                 
               
                     
                     
                   (E*T*FSDLWKLL), 
                 
                     
                     
                 
                     
                     
                   12-26 p53 protein, residues 
                 
                 
                 
               
                     
                   (SEQ ID NO: 1) 
                 
                 
                 
                 
               
                     
                     
                   (P*P*L*SQETFSDLWKLL), 
                 
             
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
               
            
           
         
       
       
         
           
           
               
               
           
         
         
            and 
         
       
       
         
           
                 
                 
               
                     
                   (SEQ ID NO. 10) 
                 
                 
                 
                 
               
                     
                     
                   XFMXXXEXLX, 
                 
             
                
               
            
             
                
               
            
           
         
         
            where X in first position is actyl moiety (CHO), X in fourth position is alpha-amino-isobutyric acid, X in fifth position is phosphonomethyl-phenylalanine, X in sixth position is 6-chlorotryptophan, X in eighth position is 1-amino-cyclopropanecarboxylic acid, X in tenth position is NH2; and 
           a membrane resident component selected from the group consisting of: 
         
       
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 3) 
                 
                 
                 
                 
               
                     
                     
                   KKWKMRRNQFWVKVQRG, 
                 
                     
                     
                   and 
                 
                     
                     
                 
                 
                 
               
                     
                   (SEQ ID NO: 12) 
                 
                 
                 
                 
               
                     
                     
                   KKWKMRRNQFWVKVQRGLLR, 
                 
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
               
            
           
         
         said membrane resident component bound to said HDM-2 binding component; 
         wherein * denotes D-amino acid, and 
         wherein selectively necrosing said cancer cell, but does not affect the normal non-cancerous cells. 
       
     
     
         2 . A method of treating cancer in a subject, said method comprising:
 providing a subject having a plurality of cancer cells; and   administering to the subject, a therapeutically effective amount of a composition including:
 an HDM-2 binding component selected from the group consisting of: 
   
       
         
           
                 
                 
                 
               
                     
                     
                   12-26 p53 protein, residues 
                 
                 
                 
               
                     
                   (SEQ ID NO: 1) 
                 
                 
                 
                 
               
                     
                     
                   (PPLSQETFSDLWKLL), 
                 
                     
                     
                 
                     
                     
                   17-26 p53 protein, residues 
                 
                 
                 
               
                     
                   (SEQ ID NO: 2) 
                 
                 
                 
                 
               
                     
                     
                   (ETFSDLWKLL), 
                 
                     
                     
                 
                     
                     
                   12-26 p53 protein, residues 
                 
                 
                 
               
                     
                   (SEQ ID NO: 1) 
                 
                 
                 
                 
               
                     
                     
                   (P*P*LSQETFSDLWKLL), 
                 
                     
                     
                 
                     
                     
                   17-26 p53 protein, residues 
                 
                 
                 
               
                     
                   (SEQ ID NO: 2) 
                 
                 
                 
                 
               
                     
                     
                   (E*T*FSDLWKLL), 
                 
                     
                     
                 
                     
                     
                   12-26 p53 protein, residues 
                 
                 
                 
               
                     
                   (SEQ ID NO: 1) 
                 
                 
                 
                 
               
                     
                     
                   (P*P*L*SQETFSDLWKLL), 
                 
                     
                     
                 
                     
                     
                   XFMXXXEXLX, 
                 
             
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
               
            
           
         
         
            where X in first position is actyl moiety (CHO), X in fourth position is alpha-amino-isobutyric acid, X in fifth position is phosphonomethyl-phenylalanine, X in sixth position is 6-chlorotryptophan, X in eighth position is 1-amino-cyclopropanecarboxylic acid, X in tenth position is NH2 (SEQ ID NO. 10; and 
           a membrane resident component selected from the group consisting of: 
         
       
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 3) 
                 
                 
                 
                 
               
                     
                     
                   K*K*WKMRRNQFWVKVQRG, 
                 
                     
                     
                 
                 
                 
               
                     
                   (SEQ ID NO: 11) 
                 
                 
                 
                 
               
                     
                     
                   K*K*WKMRRNQFWVKVQRGLLR 
                 
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
               
            
           
         
         
            wherein X is actyl moiety (CHO), and 
         
       
       
         
           
           
               
               
           
         
         said membrane resident component bound to said HDM-2 binding component; 
         wherein * denotes D-amino acid, and 
         wherein selectively necrosing said cancer cell, but does not affect the normal non-cancerous cells. 
       
     
     
         3 . The method of  claim 1 , further comprising the step of observing in a medium of the cancer cells an early release of LDH. 
     
     
         4 . The method of  claim 1 , further comprising the step of observing membranolysis of said cancer cells. 
     
     
         5 . The method of  claim 1 , further comprising the step of observing a decrease from a number of pretreatment cancer cells to a number of post treatment cancer cells. 
     
     
         6 . The method of  claim 1 , further comprising the step of repeating the administering step until a result is reached. 
     
     
         7 . The method of  claim 1 , further comprising the step of observing necrosis in the cancer cells. 
     
     
         8 . The method of  claim 1 , further comprising the step of observing a non-response in the normal cell, wherein the non-response indicates the normal cell is unaffected. 
     
     
         9 . The method of  claim 1 , wherein the administering step further comprises administering a PNC-27 (SEQ ID NO: 5) peptide, a PNC-28 (SEQ ID NO: 6) peptide, or combinations thereof. 
     
     
         10 . The method of  claim 1 , wherein the HDM-2 binding component is 12-26 p53 protein, residues 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 1) 
                 
                 
                 
                 
               
                     
                     
                   (PPLSQETFSDLWKLL), 
                 
             
                
               
            
             
                
               
            
           
         
       
     
     
         11 . The method of  claim 1 , wherein the HDM-2 binding component is 17-26 p53 protein, residues 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 2) 
                 
                 
                 
                 
               
                     
                     
                   (ETFSDLWKLL), 
                 
             
                
               
            
             
                
               
            
           
         
       
     
     
         12 . The method of  claim 1 , wherein the membrane resident component is 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 3) 
                 
                 
                 
                 
               
                     
                     
                   KKWKMRRNQFWVKVQRG 
                 
             
                
               
            
             
                
               
            
           
         
       
     
     
         13 . The method of  claim 10 , wherein the membrane resident component is 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 3) 
                 
                 
                 
                 
               
                     
                     
                   KKWKMRRNQFWVKVQRG 
                 
             
                
               
            
             
                
               
            
           
         
       
     
     
         14 . The method of  claim 11 , wherein the membrane resident component is 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 3) 
                 
                 
                 
                 
               
                     
                     
                   KKWKMRRNQFWVKVQRG 
                 
             
                
               
            
             
                
               
            
           
         
       
     
     
         15 . The method of  claim 2 , wherein the HDM-2 binding component is 12-26 p53 protein, residues 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 1) 
                 
                 
                 
                 
               
                     
                     
                   (PPLSQETFSDLWKLL) 
                 
             
                
               
            
             
                
               
            
           
         
       
     
     
         16 . The method of  claim 2 , wherein the HDM-2 binding component is 17-26 p53 protein, residues 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 2) 
                 
                 
                 
                 
               
                     
                     
                   ETFSDLWKLL) 
                 
             
                
               
            
             
                
               
            
           
         
       
     
     
         17 . The method of  claim 2 , wherein the membrane resident component is 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 3) 
                 
                 
                 
                 
               
                     
                     
                   KKWKMRRNQFWVKVQRG 
                 
             
                
               
            
             
                
               
            
           
         
       
     
     
         18 . The method of  claim 15 , wherein the membrane resident component is 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 3) 
                 
                 
                 
                 
               
                     
                     
                   KKWKMRRNQFWVKVQRG 
                 
             
                
               
            
             
                
               
            
           
         
       
     
     
         19 . The method of  claim 16 , wherein the membrane resident component is 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 3) 
                 
                 
                 
                 
               
                     
                     
                   KKWKMRRNQFWVKVQRG 
                 
             
                
               
            
             
                
               
            
           
         
       
     
     
         20 . The method of  claim 1 , wherein selective necrosis comprises pore formation.

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