Methods of identifying compounds that modulate il-4 receptor-mediated ige synthesis utilizing a c-myc protein

Abstract

The present provides compounds capable of modulating IL-4 receptor-mediated IgE production, as well as IL-4 induced processes associated therewith, methods and kits for identifying such compounds that utilize a c-Myc protein as a surrogate analyte and methods of using the compounds in a variety of in vitro, in vitro and ex vivo contexts.

1 - 24 . (canceled)  
     
     
         25 . A compound comprising a peptide or peptide analog, or a pharmaceutically acceptable salt thereof, having the formula (I): 
 wherein: 
 X 1  is a non-polar residue;  
 X 2  is a polar residue or an alanine;  
 X 3  is a basic or an aliphatic residue;  
 X 4  is a basic or an aliphatic residue;  
 X 5  is an acidic or an aliphatic residue;  
 X 6  is a hydroxyl-containing or an aliphatic residue;  
 X 7  is a cysteine-like residue or an alanine;  
 X 8  is an aliphatic residue;  
 X 9  is a hydroxyl-containing or an aliphatic residue;  
 X 10  is a basic or an aliphatic residue;  
 X 11  is a hydroxyl-containing residue;  
 X 12  is an aliphatic residue;  
 X 13  is an acidic or an aliphatic residue;  
 X 14  is an acidic or an aliphatic residue;  
 X 15  is an aliphatic residue;  
 X is a hydrophobic residue;  
 X 17  is an aliphatic residue;  
 X 18  is an aliphatic residue;  
 X 19  is a hydrophobic residue;  
 X 20  is a hydrophobic residue;  
 X 21  is an aliphatic residue;  
 X 22  is an aliphatic residue;  
 X is a conformationally constrained residue;  
 Z 1  is RRN—, RC(O)NR—, RS(O) 2 NR— or an amino-terminal blocking group;  
 Z 2  is —C(O)OR, —C(O)O—, —C(O)NRR or a carboxyl-terminal blocking group;  
 each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl;  
 each “˜” independently represents an amide, a substituted amide or an isostere of an amide;  
 each “—” represents a bond, or a 1 to 10 residue peptide or peptide analog; and  
 wherein one or more of X 1 , X 2 , X 3 , X 21 , X 22 , or X 23  may be absent.  
   
     
     
         26 . The compound of  claim 25  in which each “˜” is an amide, Z 1  is H 2 N— and Z 2  is 
 —C(O)OH or —C(O)O—.    
     
     
         27 . The compound of  claim 25  having the formula (II):  
         M˜Q˜R—R˜E˜S˜C—X 8 ˜X 9 ˜X 10 ˜S˜V˜E˜E˜G˜W˜G˜L˜F˜Y˜L˜G˜P  wherein:    X 8  is an aliphatic residue;    X 9  is a small aliphatic or a hydroxyl-containing residue; and    X 10  is a basic residue or an aliphatic residue.    
     
     
         28 . The compound of  claim 27  in which X 8  is I or A and/or X 9  is T or A.  
     
     
         29 . The compound of  claim 27  in which X 10  is R or A.  
     
     
         30 . The compound of  claim 25  which is selected from the group consisting of BR10A1wt (SEQ ID NO:1); BR10A1CI (SEQ ID NO:2); BR10A1TR (SEQ ID NO:3); 
 BR10A1MQ (SEQ ID NO:4); BR10A1RR (SEQ ID NO:5); BR10A1EE (SEQ ID NO:6);    BR10A1GW (SEQ ID NO:7); BR10A1GL (SEQ ID NO:8); BR10A1FY (SEQ ID NO:9);    BR10A1STOP (SEQ ID NO:10); BR10A1ES (SEQ ID NO:11); and BR10A10CIGW (SEQ ID NO:12) and an analog thereof.    
     
     
         31 . A compound comprising a peptide or peptide analog having the formula (IV)  
         Z 1 −M˜Q˜R˜R˜E˜S˜C˜T˜R—S˜V˜E˜E˜G˜W˜G˜L˜F˜Y˜L˜G˜P−Z 2   (IV)  wherein:    Z 1  is RRN—, RC(O)NR—, RS(O) 2 NR— or an amino-terminal blocking group;    Z 2  is —C(O)OR, —C(O)O—, —C(O)NRR or a carboxyl-terminal blocking group;    each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl;    each “˜” independently represents an amide, a substituted amide or an isostere of an amide; and    each “—” represents a bond, or a 1 to 10 residue peptide or peptide analog;    and variants thereof in which one, two, three or four of the amino acid residues set forth in IV are replaced by another amino acid selected from the same class as the original amino acid or by an Ala or a Gly residue.    
     
     
         32 . (canceled)  
     
     
         33 . A pharmaceutical composition comprising a compound according to  claim 25  or  claim 31 , and a pharmaceutically acceptable carrier, excipient or diluent.  
     
     
         34 . A pharmaceutical composition comprising a compound identified by the method of claim  1  and a pharmaceutically acceptable carrier, excipient or diluent.  
     
     
         35 . A method of modulating IL-4 receptor-mediated IgE production in a cell, comprising administering to the cell an effective amount of a compound that binds a c-Myc protein.  
     
     
         36 . The method of  claim 35  in which the compound competitively binds the c-Myc protein in the presence of an active BR10A1 compound.  
     
     
         37 . The method of  claim 35  in which the compound is selected from the group consisting of BR10A1wt (SEQ ID NO:1); BR10A1CI (SEQ ID NO:2); BR10A1TR (SEQ ID NO:3); BR10A1MQ (SEQ ID NO:4); BR10A1RR (SEQ ID NO:5); BR10A1EE (SEQ ID NO:6); BR10A1GW (SEQ ID NO:7); BR10A1GL (SEQ ID NO:8); BR10A1FY (SEQ ID NO:9); BR10A1 STOP (SEQ ID NO:10); BR10A1ES (SEQ ID NO:11); and BR10A1CIGW (SEQ ID NO:12) and an analog thereof.  
     
     
         38 . The method of  claim 35  in which the compound is identified by the method of claim  1 .  
     
     
         39 . A method of treating an animal suffering from a disease characterized by, caused by or associated with IgE production and/or accumulation and/or symptoms associated therewith, comprising administering to the animal an amount of a compound that binds a c-Myc protein effective to treat the disease.  
     
     
         40 . The method of  claim 39  in which the compound competitively binds the c-Myc protein in the presence of an active BR10A1 compound.  
     
     
         41 . The method of  claim 39  in which the compound is selected from the group consisting of BR10A1wt (SEQ ID NO:1); BR10A1CI (SEQ ID NO:2); BR10A1TR (SEQ ID NO:3); BR10A1MQ (SEQ ID NO:4); BR10A1RR (SEQ ID NO:5); BR10A1EE (SEQ ID NO:6); BR10A1GW (SEQ ID NO:7); BR10A1GL (SEQ ID NO:8); BR10A1FY (SEQ ID NO:9); BR10A1STOP (SEQ ID NO:10); BR10A1ES (SEQ ID NO:11); and BR10A1CIGW (SEQ ID NO:12) and an analog thereof.  
     
     
         42 . The method of  claim 39  in which the compound is identified by the method of claim  1 .  
     
     
         43 . The method of  claim 39  in which the disease is selected from the group consisting of an allergy, an atopic disorder, allergic rhinitis, allergic conjunctivitis, systemic mastocytosis, hyper IgE syndrome, and IgE gammopathies.  
     
     
         44 . The method of  claim 43  in which the allergy is an anaphylactic allergic reaction.  
     
     
         45 . The method of  claim 43  in which the atopic disorder is selected from the group consisting of atopic dermatitis, atopic eczema and atopic asthma.  
     
     
         46 . A kit for identifying compounds that modulate IL-4 induced IgE production, comprising a c-Myc protein or a cell expressing a c-Myc protein and a compound that competitively binds the c-Myc protein in the presence of an active BR10A1 compound.  
     
     
         47 . The kit of  claim 46  in which the compound is selected from the group consisting of BR10A1wt (SEQ ID NO:1); BR10A1CI (SEQ ID NO:2); BR10A1TR (SEQ ID NO:3); BR10A1MQ (SEQ ID NO:4); BR10A1RR (SEQ ID NO:5); BR10A1EE (SEQ ID NO:6); BR10A1GW (SEQ ID NO:7); BR10A1GL (SEQ ID NO:8); BR10A1FY (SEQ ID NO:9); BR10A1 STOP (SEQ ID NO:10); BR10A1ES (SEQ ID NO: 11); and BR10A1CIGW (SEQ ID NO: 12) and an analog thereof.  
     
     
         48 . A method of inhibiting germline c transcription in a cell, comprising administering to the cell an effective amount of a compound that binds a c-Myc protein.  
     
     
         49 . The method of  claim 48  in which the compound competitively binds the c-Myc protein in the presence of an active BR10A1 compound.  
     
     
         50 . The method of  claim 48  in which the compound is selected from the group consisting of BR10A1wt (SEQ ID NO:1); BR10A1CI (SEQ ID NO:2); BR10A1TR (SEQ ID NO:3); BR10A1MQ (SEQ ID NO:4); BR10A1RR (SEQ ID NO:5); BR10A1EE (SEQ ID NO:6); BR10A1GW (SEQ ID NO:7); BR10A1GL (SEQ ID NO:8); BR10A1FY (SEQ ID NO:9); BR10A1STOP (SEQ ID NO:10); BR10A1ES (SEQ ID NO:11); and BR10A1CIGW (SEQ ID NO:12) and an analog thereof.  
     
     
         51 . The method of  claim 49  in which the active BR10A1 compound is selected from BR10A1wt (SEQ ID NO:1); BR10A1CI (SEQ ID NO:2); BR10A1TR (SEQ ID NO:3); BR10A1MQ (SEQ ID NO:4); BR10A1RR (SEQ ID NO:5); BR10A1EE (SEQ ID NO:6); BR10A1GW (SEQ ID NO:7); BR10A1GL (SEQ ID NO:8); BR10A1FY (SEQ ID NO:9); BR10A1STOP (SEQ ID NO:10); BR10A1ES (SEQ ID NO:11); and BR10A1CIGW (SEQ ID NO:12).  
     
     
         52 . (canceled)