US2004142854A1PendingUtilityA1

Compounds and methods for stimulating beta-catenin mediated gene expression and differentiation

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Assignee: ADHEREX TECHNOLOGIES INCPriority: Apr 5, 1999Filed: Oct 21, 2003Published: Jul 22, 2004
Est. expiryApr 5, 2019(expired)· nominal 20-yr term from priority
Inventors:Orest W. BlaschukStephen W. ByersBarbara J. Gour
A61P 25/00A61P 17/14C07K 14/4705A61K 38/00
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Claims

Abstract

Modulating agents for inhibiting degradation of cytoplasmic β-catenin are provided. The modulating agents comprise one or more of: (1) the peptide sequence SYLDS(PO 4 )GIHS(PO 4 )G (SEQ ID NO:1) or (2) a peptide analogue or peptidomimetic thereof. Methods for using such modulating agents for stimulating β-catenin mediated gene expression and cellular differentiation are provided.

Claims

exact text as granted — not AI-modified
What is claimed is:  
     
         1 . A method for stimulating activation of gene transcription in a cell, comprising contacting a cell with a modulating agent capable of inhibiting degradation of cytoplasmic β-catenin, wherein the agent comprises an internalization moiety and one or more of: 
 (a) the amino acid sequence SYLDS(PO 4 )GIHS(PO 4 )G (SEQ ID NO:1); or  
 (b) a peptide analogue or peptidomimetic of the amino acid sequence SYLDS(PO 4 )GIHS(PO 4 )G (SEQ ID NO:1);  
 and thereby stimulating activation of gene transcription in the cell.  
 
     
     
         2 . A method according to  claim 1 , wherein the modulating agent comprises the linear peptide sequence SYLDS(PO 4 )GIHS(PO 4 )G (SEQ ID NO:1).  
     
     
         3 . A method according to  claim 1 , wherein the internalization moiety is a peptide internalization sequence.  
     
     
         4 . A method according to  claim 3 , wherein the internalization sequence comprises a sequence selected from the group consisting of RQIKIWFQNRRMKWKK (SEQ ID NO:9), RQIKIWPQNRRNKWKK (SEQ ID NO:10) and YGRKKRRQRRR (SEQ ID NO:14).  
     
     
         5 . A method according to  claim 4 , wherein the modulating agent has the sequence YGRKKRRQRRRGSYLDS(PO 4 )GIHS(PO 4 )G (SEQ ID NO:15).  
     
     
         6 . A method according to  claim 4 , wherein the modulating agent has the sequence SYLDS(PO 4 )GIHS(PO 4 )GRQIKIWPQNRRNKWKK (SEQ ID NO:12).  
     
     
         7 . A method according to  claim 1 , wherein the internalization moiety is a liposome.  
     
     
         8 . A method according to  claim 1 , wherein the internalization moiety is an antibody or ligand that specifically binds to a cell surface receptor.  
     
     
         9 . A method according to  claim 1 , wherein the modulating agent is linked to a targeting agent.  
     
     
         10 . A method according to  claim 1 , wherein the modulating agent is present within a pharmaceutical composition comprising a pharmaceutically acceptable carrier.  
     
     
         11 . A method according to  claim 1 , wherein the activation of gene transcription is mediated by a member of the Wnt signaling cascade.  
     
     
         12 . A method for stimulating differentiation of a cell, comprising contacting a cell with a modulating agent capable of inhibiting degradation of cytoplasmic β-catenin, wherein the agent comprises an internalization moiety and one or more of: 
 (a) the amino acid sequence SYLDS(PO 4 )GIHS(PO 4 )G (SEQ ID NO:1); or  
 (b) a peptide analogue or peptidomimetic of the amino acid sequence SYLDS(PO 4 )GIHS(PO 4 )G (SEQ ID NO:1);  
 and thereby stimulating differentiation of the cell.  
 
     
     
         13 . A method according to  claim 12 , wherein the modulating agent comprises the linear peptide sequence SYLDS(PO 4 )GIHS(PO 4 )G (SEQ ID NO:1).  
     
     
         14 . A method according to  claim 12 , wherein the internalization moiety is an internalization sequence.  
     
     
         15 . A method according to  claim 14 , wherein the internalization sequence comprises a sequence selected from the group consisting of RQIKIWFQNRRMKWKK (SEQ ID NO:9), RQIKIWPQNRRNKWKK (SEQ ID NO:10) and YGRKKRRQRRR (SEQ ID NO:14).  
     
     
         16 . A method according to  claim 15 , wherein the modulating agent has the sequence YGRKKRRQRRRGSYLDS(PO 4 )GIHS(PO 4 )G (SEQ ID NO:15).  
     
     
         17 . A method according to  claim 15 , wherein the modulating agent has the sequence SYLDS(PO 4 )GIHS(PO 4 )GRQIKIWPQNRRNKWKK (SEQ ID NO:12).  
     
     
         18 . A method according to  claim 12 , wherein the internalization moiety is a liposome.  
     
     
         19 . A method according to  claim 12 , wherein the internalization moiety is an antibody or ligand that specifically binds to a cell surface receptor.  
     
     
         20 . A method according to  claim 12 , wherein the modulating agent is linked to a targeting agent.  
     
     
         21 . A method according to  claim 12 , wherein the modulating agent is present within a pharmaceutical composition comprising a pharmaceutically acceptable carrier.  
     
     
         22 . A method according to  claim 12 , wherein the cell is a skin cell.  
     
     
         23 . A method according to  claim 12 , wherein the cell is a keratinocyte.  
     
     
         24 . A method for stimulating hair growth on a mammal, comprising administering to a mammal a modulating agent capable of inhibiting degradation of cytoplasmic β-catenin, wherein the agent comprises an internalization moiety and one or more of: 
 (a) the amino acid sequence SYLDS(PO 4 )GIHS(PO 4 )G (SEQ ID NO:1); or  
 (b) a peptide analogue or peptidomimetic of the amino acid sequence SYLDS(PO 4 )GIHS(PO 4 )G (SEQ ID NO:1);  
 and thereby stimulating hair growth or reducing hair loss on the mammal.  
 
     
     
         25 . A method according to  claim 24 , wherein the modulating agent comprises the linear peptide sequence SYLDS(PO 4 )GIHS(PO 4 )G (SEQ ID NO:1).  
     
     
         26 . A method according to  claim 24 , wherein the internalization moiety is an internalization sequence.  
     
     
         27 . A method according to  claim 26 , wherein the internalization sequence comprises a sequence selected from the group consisting of RQIKIWFQNRRMKWKK (SEQ ID NO:9), RQIKIWPQNRRNKWKK (SEQ ID NO:10) and YGRKKRRQRRR (SEQ ID NO:14).  
     
     
         28 . A method according to  claim 27 , wherein the modulating agent has the sequence YGRKKRRQRRRGSYLDS(PO 4 )GIHS(PO 4 )G (SEQ ID NO:15).  
     
     
         29 . A method according to  claim 27 , wherein the modulating agent has the sequence SYLDS(PO 4 )GIHS(PO 4 )GRQIKIWPQNRRNKWKK (SEQ ID NO:12).  
     
     
         30 . A method according to  claim 24 , wherein the internalization moiety is a liposome.  
     
     
         31 . A method according to  claim 24 , wherein the internalization moiety is an antibody or ligand that specifically binds to a cell surface receptor.  
     
     
         32 . A method according to  claim 24 , wherein the modulating agent is linked to a targeting agent.  
     
     
         33 . A method according to  claim 24 , wherein the modulating agent is present within a pharmaceutical composition comprising a pharmaceutically acceptable carrier.  
     
     
         34 . A method according to  claim 24 , wherein the step of administering comprises contacting skin cells with the modulating agent.  
     
     
         35 . A method according to  claim 34 , wherein the skin cells are present on the scalp of the mammal.  
     
     
         36 . A method according to  claim 34 , wherein the skin cells are present within the ear of the mammal.  
     
     
         37 . A method for stimulating exfoliation of skin on a mammal, comprising administering to a mammal a modulating agent capable of inhibiting degradation of cytoplasmic β-catenin, wherein the agent comprises an internalization moiety and one or more of: 
 (a) the amino acid sequence SYLDS(PO 4 )GIHS(PO 4 )G (SEQ ID NO:1); or  
 (b) a peptide analogue or peptidomimetic of the amino acid sequence SYLDS(PO 4 )GIHS(PO 4 )G (SEQ ID NO:1);  
 and thereby stimulating exfoliation of skin on the mammal.  
 
     
     
         38 . A method according to  claim 37 , wherein the modulating agent comprises the linear peptide sequence SYLDS(PO 4 )GIHS(PO 4 )G (SEQ ID NO:1).  
     
     
         39 . A method according to  claim 37 , wherein the internalization moiety is an internalization sequence.  
     
     
         40 . A method according to  claim 39 , wherein the internalization sequence comprises a sequence selected from the group consisting of RQIKIWFQNRRMKWKK (SEQ ID NO:9), RQIKIWPQNRRNKWKK (SEQ ID NO:10) and YGRKKRRQRRR (SEQ ID NO:14).  
     
     
         41 . A method according to  claim 40 , wherein the modulating agent has the sequence YGRKKRRQRRRGSYLDS(PO 4 )GIHS(PO 4 )G (SEQ ID NO:15).  
     
     
         42 . A method according to  claim 40 , wherein the modulating agent has the sequence SYLDS(PO 4 )GIHS(PO 4 )GRQIKIWPQNRRNKWKK (SEQ ID NO:12).  
     
     
         43 . A method according to  claim 37 , wherein the internalization moiety is a liposome.  
     
     
         44 . A method according to  claim 37 , wherein the internalization moiety is an antibody or ligand that specifically binds to a cell surface receptor.  
     
     
         45 . A method according to  claim 37 , wherein the modulating agent is linked to a targeting agent.  
     
     
         46 . A method according to  claim 37 , wherein the modulating agent is present within a pharmaceutical composition comprising a pharmaceutically acceptable carrier.  
     
     
         47 . A method according to  claim 37 , wherein the step of administering comprises contacting skin cells with the modulating agent.

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