Novel tumor-targeting compounds

Abstract

The invention relates to a novel compounds targeting human cancer cells, a method for synthesis of such compounds, and use of such compounds in treating cancer.

1 . A synthetic non-immunoglobulin antitumor compound relating to the structure of an immunoglobulin, the compound comprising,
 (a) two or more peptides as binders, each comprising a sequence capable of binding to tumor cell markers including human Epidermal Growth Factor Receptor (EGFR); human Vascular Endothelia Growth Factor Receptor (VEGFR); ErbB-2 receptor (Her-2); Fibroblast Growth Factor Receptor (FGFR); integrins, including alpha-3-beta-1 integrin and alpha-4-beta-1 integrin; lectins, including human beta-galactoside-binding lectin 3 (Galectin-3, or Gal-3) or c-Met (hepatocyte growth factor receptor, HGFR or scatter factor, SF);   (b) at least one peptide as effector comprising one of the following sequences SEQ ID NO 24; SEQ ID NO 25; SEQ ID NO 26; and   (c) two or more linker molecules composed of a polypeptide, of polyethylene glycol, or of a combination thereof, whereby the linker molecules covalently link the two or more binders to the at least one effector to relate to the structure of an immunoglobulin molecule.   
     
     
         2 . The synthetic non-immunoglobulin antitumor compound according to  claim 1  wherein
 (c) the two or more peptides as binders, each comprising one of the following sequences: SEQ ID NO 1; SEQ ID NO 2; SEQ ID NO 3, SEQ ID NO 4 SEQ ID NO 7; SEQ ID NO 8; SEQ ID NO 9; SEQ ID NO 10; SEQ ID NO 11; SEQ ID NO 12; SEQ ID NO 13; SEQ ID NO 14; or a derivative or variation thereof which is capable of binding to human Epidermal Growth Factor Receptor (EGFR); human Vascular Endothelia Growth Factor Receptor (VEGFR); ErbB-2 receptor (Her-2); Fibroblast Growth Factor Receptor (FGFR); integrins, including alpha-3-beta-1 integrin and alpha-4-beta-1 integrin; lectins, including human beta-galactoside-binding lectin 3 (Galectin-3, or Gal-3); c-Met (hepatocyte growth factor receptor, HGFR or scatter factor, SF); wherein 
 (d) the at least one peptide as effector comprising one of the following sequences SEQ ID NO 24; SEQ ID NO 25; SEQ ID NO 26; and 
 (c) two or more linker molecules composed of a polypeptide, of polyethylene glycol, or of a combination thereof,
 whereby the linker molecules covalently link the two or more binders to the at least one effector. 
 
 
     
     
         3 . The antitumor compound according to  claim 1  having the formula: (Binder-Linker)2-Effector, wherein
 (a) the binder peptides comprise the sequence SEQ ID NO 1 or a variation or derivative thereof capable of binding to EGFR; 
 (b) the effector peptide comprises one of the following sequences: SEQ ID NO 24; SEQ ID NO 25; SEQ ID NO 26 at the N terminus as well as two lysine residues; 
 (c) the linker molecules are polyethylene glycol oligomers; 
 (d) the effector is covalently attached via the epsilon amino groups of the two lysine residues through an amide bond to terminal carboxy groups of the two linker molecules; 
 (e) the binder molecules are covalently attached via the carboxy terminus through an amide bond to a terminal carboxy group of the polyethylene glycol linker molecules. 
 
     
     
         4 . The antitumor compound according to  claim 1 , wherein
 (a) the binder peptide has the sequence of SEQ ID NO 1;   (b) the effector peptide has one of the following sequences SEQ ID NO 39; SEQ ID NO 40; SEQ ID NO 41;   (c) the two linker molecules are polyethylene glycol oligomers with a length between 2 and 100 ethylene glycol units.   
     
     
         5 . An antitumor compound having comprising a the following structure according to  FIG. 2 . 
       
         
           
           
               
               
           
         
       
     
     
         6 . An antitumor compound having comprising a the following structure according to  FIG. 3 . 
       
         
           
           
               
               
           
         
       
     
     
         7 . An antitumor compound comprising the following structure. 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         8 . The antitumor compound according to  claim 1  wherein the amino terminal ends of the peptide sequences of the binders are acetylated to increase stability. 
     
     
         9 . A pharmaceutical composition comprising a compound according to  claim 1 . 
     
     
         10 . A method of treating of a pharmaceutical colon cancer, head and neck cancer, ovarial cancer, pancreatic cancer, non-small cell lung cancer, breast cancer or glioblastoma cells that carry the EGFR marker, in a patient in need thereof, said method comprising administering to said patient an effective amount of the pharmaceutical composition according to  claim 9 . 
     
     
         11 . A method of treating breast cancer, pancreatic cancer, ovarian cancer, NSCLC or lymphoma or other pathogenic cells that carry an ErbB-2 receptor (Her-2), in a patient in need thereof, said method comprising administering to said patient an effective amount of the pharmaceutical composition according to  claim 9 . 
     
     
         12 . A method of treating ovarian cancer Of cells that carry a Fibroblast Growth Factor Receptor (FGF receptor), in a patient in need thereof, said method comprising administering to said patient an effective amount of the pharmaceutical composition according to  claim 9 . 
     
     
         13 . A method of treating multiple peritoneal tumors of gastric cancer cells that carry an Integrin including Alpha-3-beta-1 Integrin and Alpha-4-beta-1 Integrin, in a patient in need thereof, said method comprising administering to said patient an effective amount of the pharmaceutical composition according to  claim 9 . 
     
     
         14 . A method of treating breast cancer cells that carry the human beta-galactoside-binding lectin Galectin-3 (Gal-3), in a patient in need thereof, said method comprising administering to said patient an effective amount of the pharmaceutical composition according to  claim 9 . 
     
     
         15 . A method of treating human cancers that have a VEGFR, in a patient in need thereof, said method comprising administering to said patient an effective amount of the pharmaceutical composition according to  claim 9 . 
     
     
         16 . A method of treating pathogenic cells that carry the EGFR marker other than colon cancer, head and neck cancer, ovarian, cancer, pancreatic cancer, non-small cell lung cancer, breast cancer or glioblastoma cells, in a patient in need of treatment by administering an effective amount of a with the pharmaceutical composition according to  claim 9 . 
     
     
         17 . A method of treating pathogenic Cells that carry the ErbB-2 receptor/(Her-2), other than colon cancer, head and neck cancer, ovarian, cancer, pancreatic cancer, non-small cell lung cancer, breast cancer or glioblastoma cells, in a patient in need of treatment by administering an effective amount of a with the pharmaceutical composition according to  claim 9 . 
     
     
         18 . A method of treating pathogenic cells that carry a Fibroblast Growth Factor Receptor (FGF receptor), other than colon cancer, head and neck cancer, ovarian, cancer, pancreatic cancer, non-small cell lung cancer, breast cancer or glioblastoma cells, in a patient in need of treatment by administering an effective amount of a with the pharmaceutical composition according to  claim 9 . 
     
     
         19 . A method of treating pathogenic cells that carry an Integrin including Alpha-3-beta-1 Integrin and Alpha-4-beta-1 Integrin, other than colon cancer, head and neck cancer, ovarian, cancer, pancreatic cancer, non-small cell lung cancer, breast cancer or glioblastoma cells, in a patient in need of treatment by administering an effective amount of a with the pharmaceutical composition according to  claim 9 . 
     
     
         20 . A method of treating pathogenic cells that carry the human beta-galactoside-binding lectin Galectin-3 (Gal-3), other than colon cancer, head and neck cancer, ovarian, cancer, pancreatic cancer, non-small cell lung cancer, breast cancer or glioblastoma cells, in a patient in need of treatment by administering an effective amount of a with the pharmaceutical the composition according to  claim 9 .