Protein kinase inhibitors comprising atp mimetics conjugated to peptides or peptidomimetics

Abstract

The present invention provides small molecules having high affinity to the ATP binding site of protein kinases, which are conjugated to apeptide or peptidomimetic moiety which mimics the substrate of PKB. The chimeric compounds according to the present invention preferably serve as PKB inhibitors with improved activity and selectivity. Novel ATP mimetic compounds, particularly isoquinoline derivatives, conjugated with peptides or peptidomimetics are useful as inhibitors of protein kinases for experimental, medical, and drug design purposes. Furthermore, pharmaceutical compositions comprising these protein kinase inhibitors, and methods of using such compositions for treatment and diagnosis of cancers, diabetes, cardiovascular pathologies, hemorrhagic shock, obesity, inflammatory diseases, diseases of the central nervous system, and autoimmune disease, are disclosed.

1 . A protein kinase inhibitor comprising a peptide having the sequence 
 Arg-Pro-Arg-R 4 —R 5 —R 6 —R 7      wherein:    R 4  is selected from the group consisting of: norvaline, valine, methionine, omithine, arginine and norleucine;    R 5  is selected from the group consisting of: tyrosine, threonine, aminobutyric acid and glutamic acid;    R 6  is selected from the group consisting of: diaminopropionic acid, alanine, aminobutyric acid, aspartic acid and diaminobutyric acid; and    R 7  is selected from the group consisting of: homoleucine, phenylalanine and norleucine.    
     
     
         2 . The protein kinase inhibitor according to  claim 1  wherein: 
 R 4  is norvaline;    R 5  is tyrosine;    R 6  is diaminopropionic acid; and    R 7  is homoleucine.    
     
     
         3 . The protein kinase inhibitor according to  claim 1  further comprising a moiety W-L connected to a group selected from the group consisting of: the peptide's amino terminus, the peptide's carboxy terminus, a side chain of A 4 , A 5 , R 6  or A 7 ; wherein W is an hydrophobic moiety, capable of improving cell permeability; and L is i) a bond selected from the group consisting of: amide, amine, urea, carbamate, hydrazine, sulfonamide; or ii) at least one amino acid selected from the group consisting of: glycine, β-alanine, phenylalanine, aminobutyric acid and aminopentanoic acid.  
     
     
         4 . The protein kinase inhibitor according to  claim 3  wherein W is selected from the group consisting of: substituted or unsubstituted alkylene, aliphatic, aromatic or heterocyclic moiety, of 1-18 carbon atoms; and L is selected from the group consisting of an amide bond, glycine and β-alanine.  
     
     
         5 . The compound according to  claim 4  wherein W is selected from the group consisting of: myristyl, lauryl, 5-mercaptoaminopropyl-isoquinoline and 5-aminoethylsulfonamide isoquinoline.  
     
     
         6 . The compound according to  claim 5  selected from the group consisting of: 
 Lauryl-Gly-Arg-Pro-Arg-Nva-Tyr-Dap-Hol;    Lauryl-β-Ala-Arg-Pro-Arg-Nva-Tyr-Dap-Hol;    Myristyl-Arg-Pro-Arg-Nva-Tyr-Dap-Hol;    Myristyl-Gly-Arg-Pro-Arg-Nva-Tyr-Dap-Hol;    Myristyl-β-Ala-Arg-Pro-Arg-Nva-Tyr-Dap-Hol.    
     
     
         7 . A pharmaceutical composition comprising as an active ingredient A protein kinase inhibitor comprising a peptide having the sequence 
 Arg-Pro-Arg-R 4 —R 5 —R 6 —R 7      wherein:    R 4  is selected from the group consisting of: norvaline, valine, methionine, omithine, arginine and norleucine;    R 5  is selected from the group consisting of: tyrosine, threonine, aminobutyric acid and glutamic acid;    R 6  is selected from the group consisting of: diaminopropionic acid, alanine, aminobutyric acid, aspartic acid and diaminobutyric acid; and    R 7  is selected from the group consisting of: homoleucine, phenylalanine and norleucine.    
     
     
         8 . The pharmaceutical composition according to  claim 7  wherein: 
 R 4  is norvaline;    R 5  is tyrosine;    R 6  is diaminopropionic acid;    R 7  is homoleucine; and    a pharmaceutically acceptable diluent or carrier.    
     
     
         9 . The pharmaceutical composition according to  claim 7  wherein the peptide further comprises a moiety W-L connected to a group selected from the group consisting of: the peptide's amino terminus, the peptide's carboxy terminus, a side chain of A 4 , A 5 , R 6  or A 7 ; wherein W is an hydrophobic moiety, capable of improving cell permeability; and L is i) a bond selected from the group consisting of: amide, amine, urea, carbamate, hydrazine, sulfonamide; or ii) at least one amino acid selected from the group consisting of: glycine, β-alanine, phenylalanine, aminobutyric acid and aminopentanoic acid.  
     
     
         10 . The pharmaceutical composition according to  claim 9  wherein W is selected from the group consisting of: substituted or unsubstituted alkylene, aliphatic, aromatic or heterocyclic moiety, of 1-18 carbon atoms; and L is selected from the group consisting of an amide bond, glycine and β-alanine.  
     
     
         11 . The pharmaceutical composition according to  claim 10  wherein W is selected from the group consisting of: myristyl, lauryl, 5-mercaptoaminopropyl-isoquinoline and 5-aminoethylsulfonamide isoquinoline.  
     
     
         12 . The pharmaceutical composition according to  claim 11  wherein the peptide is selected from the group consisting of: 
 Lauryl-Gly-Arg-Pro-Arg-Nva-Tyr-Dap-Hol;    Lauryl-β-Ala-Arg-Pro-Arg-Nva-Tyr-Dap-Hol;    Myristyl-Arg-Pro-Arg-Nva-Tyr-Dap-Hol;    Myristyl-Gly-Arg-Pro-Arg-Nva-Tyr-Dap-Hol;    Myristyl-β-Ala-Arg-Pro-Arg-Nva-Tyr-Dap-Hol.    
     
     
         13 . A method of preparing a medicament for treatment of a disease selected from the group consisting of: cancer, diabetes, cardiovascular pathology, hemorrhagic shock, obesity, inflammatory disease, disease of the central nervous system, and autoimmune disease, which comprises incorporating a compound according to  claim 1  in a pharmaceutical composition, optionally with a pharmaceutically acceptable diluent or excipient.