Protein kinase signalling

Abstract

The present invention provides a method of selecting or designing a compound for the ability to regulate JAK activity. The method comprises assessing the ability of the compound to modulate the interaction of the pseudo-substrate loop (PSL) with the kinase like domaain (KLD) of JAK. In addition the present invention provides compounds which inhibit JAK and methods of treatment of JAK-associated disease states.

1 . A method of selecting or designing a compound for the ability to regulate JAK activity, the method comprising assessing the ability of the compound to modulate the interaction of the pseudo-substrate loop (PSL) with the kinase like domain (KLD) of JAK.  
     
     
         2 . A method of selecting, or designing, a compound which regulates JAK activity, the method comprising 
 (i) selecting or designing a compound which has a conformation and polarity such that it interacts with at least one ligand selected from the group consisting of residues 667-679, 711-726 and 757-765 of human JAK2 and corresponding regions of JAK family members; and    (ii) testing the compound for the ability to interfere with the binding of the PSL with the KLD.    
     
     
         3 . A method as claimed in  claim 1  or  claim 2  in which the method comprises selecting or designing a compound which has a conformation and polarity such that it interacts with at least one ligand selected from the group consisting of residues 673, 677, 711-715, 718, 724, 759 and 760 of human JAK2 and corresponding regions of JAK family members.  
     
     
         4 . A method as claimed in  claim 1  or  claim 2  in which the method comprises selecting or designing a compound which has a conformation and polarity such that it interacts with at least two ligands selected from the group consisting of residues 673, 677, 711-715, 718, 724, 759 and 760 of human JAK2 and corresponding regions of JAK family members.  
     
     
         5 . A method as claimed in  claim 1  or  claim 2  in which the method comprises selecting or designing a compound which has a conformation and polarity such that it interacts with at least three selected from the group consisting of residues 673, 677, 711-715, 718, 724, 759 and 760 of human JAK2 and corresponding regions of JAK family members.  
     
     
         6 . A method as claimed in  claim 1  or  claim 2  in which the method comprises selecting or designing a compound which has a conformation and polarity such that it interacts with at least four ligands selected from the group consisting of residues 673, 677, 711-715, 718, 724, 759 and 760 of human JAK2 and corresponding regions of JAK family members.  
     
     
         7 . A compound which interacts with the PSL or the KLD such as to interfere with the binding of the PSL with the KLD such that the activity of the JAK is reduced when compared to that of the JAK in the absence of the compound.  
     
     
         8 . A compound as claimed in  claim 7  in which the compound binds to the substrate-binding cleft of the KLD such as to interfere with or prevent the binding of the PSL to the KLD.  
     
     
         9 . A compound as claimed in  claim 7  or  claim 8  in which the compound has a conformation and polarity such that it binds to at least ligand selected from the group consisting of residues 667-679, 711-726 and 757-765 of human JAK2.  
     
     
         10 . A compound as claimed in any one of  claims 7  to  9  in which the compound binds to at least one ligand selected from the group consisting of residues 673, 677, 711-715, 718, 723-724, 759 and 760 of human JAK2.  
     
     
         11 . A compound as claimed in any one of claims  7 , to  9  in which the compound binds to at least two ligands selected from the group consisting of residues 673, 677, 711-715, 718, 723-724, 759 and 760 of human JAK2.  
     
     
         12 . A compound as claimed in any one of  claims 7  to  9  in which the compound binds to at least three ligands selected from the group consisting of residues 673, 677, 711-715, 718, 723-724, 759 and 760 of human JAK2.  
     
     
         13 . A compound as claimed in any one of claims  7  to 9 in which the compound binds to at least four ligands selected from the group consisting of residues 673, 677, 711-715, 718, 723-724, 759 and 760 of human JAK2.  
     
     
         14 . A compound as claimed in any one claims  7  to 13 in which the compound is comprised at least in part of amino acids.  
     
     
         15 . A compound as claimed in  claim 14  in which the amino acids are derived from the sequence of the PSL.  
     
     
         16 . A compound as claimed in  claim 14  or  claim 15  in which the compound is a peptide.  
     
     
         17 . A compound as claimed in  claim 16  in which the peptide is cyclic.  
     
     
         18 . A therapeutic composition comprising an compound as claimed in any one of  claims 7  to  17 .  
     
     
         19 . A compound which regulates JAK, the compound having the same or similar physico-chemical properties to a peptide comprising following amino acid sequence:  
       X1-X2-X3-X4-X5-X6-X7-X8  
       in which: 
 X1 is any amino acid, preferably proline or glycine;  
 X2 is any amino acid, preferably alanine, valine, leucine or isoleucine;  
 X3 is any amino acid, preferably glutamate or aspartate;  
 X4 is phenylalanine or tyrosine, preferably phenylalanine;  
 X5 is leucine or methionine or isoleucine;  
 X6 is arginine or lysine;  
 X7 is methionine or leucine or isoleucine, preferably methionine;  
 X8 is isoleucine or leucine or methionine, preferably isoleucine.  
 
     
     
         20 . A compound as claimed in  claim 19  in which the compound has the same or similar physico-chemical properties to the peptide PAEFMRMI.  
     
     
         21 . A compound as claimed in  claim 19  or  20  in which the compound is a peptide comprising the following amino acid sequence:  
       X1-X2-X3-X4-X5-X6-X7-X8  
       in which X1 is any amino acid, preferably proline or glycine; 
 X2 is any amino acid, preferably alanine, valine, leucine or isoleucine;  
 X3 is any amino acid, preferably glutamate or aspartate;  
 X4 is phenylalanine or tyrosine, preferably phenylalanine;  
 X5 is leucine or methionine or isoleucine;  
 X6 is arginine or lysine;  
 X7 is methionine or leucine or isoleucine, preferably methionine;  
 X8 is isoleucine or leucine or methionine, preferably isoleucine.  
 
     
     
         22 . A compound as claimed in any one of  claims 19  to  21  in which the compound is the peptide PAEFMRMI.  
     
     
         23 . A compound obtained by the method of any one of  claims 1  to  6 .  
     
     
         24 . A method of treating a subject suffering from a JAK-associated disease state, the method comprising administering to the subject a compound as claimed in any one of  claims 7  to  23 .  
     
     
         25 . A method as claimed in  claim 24  in which the JAK-associated disease stateis selected from the group consisting of Asthma, Eczema, Food Allergy, Inflammatory Bowel Disease, Crohn's Disease, Leukaemia, Lymphoma, Cutaneous Inflammation, Immune Suppression By Solid Tumour and Prostate Cancer.  
     
     
         26 . The use of a compound as claimed in any of  claims 7  to  23  in the preparation of a medicament for the treatment of a JAK-associated disease state.  
     
     
         27 . A method of designing or selecting a compound which modulates JAK activity, the method comprising subjecting a compound obtained by a method as claimed in any one of  claims 1  to  6  to biological screens and assessing the ability of the compound to modulate JAK activity.