Inhibitors of protein kinases and uses thereof

Abstract

Compounds that are capable of inhibiting the activity of one or more protein kinases are provided. The compounds are short, predominantly basic peptidic compounds comprising between about 5 and about 20 amino acids, and can optionally comprise an ATP mimetic moiety. The protein kinase inhibiting compounds can be used to inhibit the activity of one or more protein kinases in vitro or in vivo. Also provided are methods of inhibiting a protein kinase in a subject by administration of an effective amount of a protein kinase inhibiting compound and the use of the protein kinase inhibiting compounds, alone or in combination with other chemotherapeutic agents, in the treatment of protein kinase mediated diseases and disorders.

1 . A peptidic compound comprising between about 5 and about 20 amino acids and having the general Formula (I):
   (C1)J(M)-N y B z A x B y N y B x   (I)
   
       wherein:
 C1 is N x B y (A/N) x  B y N y  and is attached to J by a peptide bond from the N- or C-terminus of C1; 
 J is 1-4 amino acid residues selected from the group consisting of Cys, Lys, and His; 
 M is absent or an ATP mimetic moiety optionally linked to an amino acid selected from the group consisting of Ile, Leu, Val, and Gly, and is attached to J via the side chain or the N-terminus of one of the Lys residues of J or the N-terminus of one of the Cys residues of J; 
 each N is independently Ala, Ile, Leu, Val or Gly; 
 each B is independently Arg, Lys or Tyr; 
 each A is independently Phe, H is or Trp; 
 each x is independently 0-1; 
 each y is independently 0-2; 
 z=0-3; and 
 the sequence N y B z A x B y N y B x  is 2 or more amino acids in length, wherein: 
 when J comprises one or no Cys residues, the compound of Formula (I) comprises a single peptide chain and C1 is attached to the N-terminal amino acid of J via a peptide bond from the C-terminus of C1, and 
 when J comprises two or more Cys residues, at least two of the Cys residues are linked by a disulphide bond and the compound of Formula (I) thereby comprises a first peptide chain comprising a first of said at least two Cys residues and C1, and a second peptide chain comprising a second of said at least two Cys residues and the sequence —N y B z A x B y N y B x , 
 wherein if M is absent, the sequence —N y B z A x B y N y B x  contains at least one of Phe or Trp; and 
 wherein said peptidic compound is capable of inhibiting one or more protein kinases. 
 
     
     
         2 . The peptidic compound according to  claim 1 , wherein said peptidic compound comprises a modified N-terminus and/or C-terminus. 
     
     
         3 . The peptidic compound according to  claim 1 , wherein one of said protein kinases is protein kinase C alpha. 
     
     
         4 . The peptidic compound according to  claim 1 , wherein said peptidic compound is of Formula (II):
   (C1)J(M)-N y B z A x B y N y   (II)
   
       wherein:
 C1 is N x B y (A/N) x  B y N y  and is attached to J by a peptide bond from the N- or C-terminus of C1; 
 J is 1-4 amino acid residues selected from the group consisting Cys, Lys, and His; 
 M is absent or an ATP mimetic moiety optionally linked to an amino acid selected from the group consisting of Ile, Leu, Val, and Gly, and is attached to J via the side chain or the N-terminus of one of the Lys residues of J or the N-terminus of one of the Cys residues of J; 
 each N is independently Ala, Ile, Leu, Val or Gly; 
 each B is independently Arg, Lys or Tyr; 
 each A is independently Phe, His or Trp; 
 each x is independently 0-1; 
 each y is independently 0-2; 
 z=0-3; and 
 the sequence N y B z A x B y N y  is 2 or more amino acids in length, and wherein: 
 when J comprises one or no Cys residues, the compound of Formula (I) comprises a single peptide chain and C1 is attached to the N-terminal amino acid of J via a peptide bond from the C-terminus of C1, and 
 when J comprises two or more Cys residues, at least two of the Cys residues are linked by a disulphide bond and the compound of Formula (I) thereby comprises a first peptide chain comprising a first of said at least two Cys residues and C1, and a second peptide chain comprising a second of said at least two Cys residues and the sequence —N y B z A x B y N y B x . 
 
     
     
         5 . The peptidic compound according to  claim 1 , wherein said peptidic compound is of Formula (III):
   (C2)J(M)-N y B z A x B y N y   (III)
   
       wherein:
 C2 is B y (A/N) x  B y N y  and is attached to J by a peptide bond from the N- or C-terminus of C2; 
 J comprises two Cys residues and optionally 1-2 residues selected from the group consisting of His, and Lys; 
 the Cys residues are linked by a disulphide bond and the compound of Formula (I) thereby comprises a first peptide chain comprising a first of said two Cys residues and C2, and a second peptide chain comprising a second of said two Cys residues and the sequence —N y B z A x B y N y B x , wherein 
 M is an ATP mimetic moiety optionally linked to an amino acid selected from the group of Ile, Leu, Val or Gly and is attached to J via the N-terminus of one of the Cys residues; 
 each N is independently Ala, Ile, Leu, Val or Gly; 
 each B is independently Arg, Lys or Tyr; and 
 each A is independently Phe, His or Trp; 
 each x is independently 0-1; 
 each y is independently 0-2; and 
 z is 0-3. 
 
     
     
         6 . The peptidic compound according to  claim 1 , wherein said peptidic compound is of Formula (IV):
   N x B y (A/N) x B y N y -J(M)-N y B z A x B y N y B x   (IV)
   
       wherein:
 J is 1-2 Lys residues or a Cys residue; 
 M is absent or is an ATP mimetic moiety attached to J via the side chain of one of the Lys residues or the N-terminus of the cysteine residue; 
 each N is independently Ala, Ile, Leu, Val or Gly; 
 each B is independently Arg, Lys or Tyr; 
 each A is independently Phe, His or Tip; 
 each x is independently 0-1; 
 each y is independently 0-2; and 
 z is 0-3. 
 
     
     
         7 . The peptidic compound according to  claim 1 , wherein said peptidic compound is selected from the group consisting of (Compound 1 disclosed as SEQ ID NOS 48 and 49, Compounds 2-15 disclosed as SEQ ID NOS 30-43, Compound 16 disclosed as SEQ ID NOS 44 and 50, Compound 17 disclosed as SEQ ID NO: 44, Compound 18 disclosed as SEQ ID NOS 48 and 18 and Compound 19 disclosed as SEQ ID NOS 44 and 49, all respectively, in order of appearance): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         8 . A composition comprising the peptidic compound according to  claim 1 , and a pharmaceutically acceptable diluent or carrier. 
     
     
         9 - 22 . (canceled) 
     
     
         23 . A method of inhibiting a protein kinase in a subject comprising administering to said subject an effective amount of the peptidic compound according to  claim 1 . 
     
     
         24 . The method according to  claim 23 , wherein said protein kinase is selected from the group of: a PKCα isoform, MAPKp38, protein kinase B and protein kinase A. 
     
     
         25 . A method of inhibiting the proliferation of cancer cells comprising contacting said cancer cells with an effective amount of the peptidic compound according to  claim 1 . 
     
     
         26 - 27 . (canceled) 
     
     
         28 . A method of treating a protein kinase mediated disease or disorder in a subject comprising administering to said subject an effective amount of the peptidic compound according to  claim 1 . 
     
     
         29 . The method according to  claim 28 , wherein said protein kinase mediated disease or disorder is cancer, psoriasis, angiogenesis, restenosis, atherosclerosis, cardiovascular disease, hypertension, diabetes, a neurological disorder, rheumatoid arthritis, a kidney disorder, an inflammatory disorder or an autoimmune disorder. 
     
     
         30 . (canceled)