Modulation of beta-catenin/TCF-activated transcription

• US 20050059628A1
• Filed: 08/27/2004
• Published: 03/17/2005
• Est. Priority Date: 08/28/2003
• Status: Active Grant

• Current Assignee: Choongwae Pharma Corporation
• Original Assignee: Choongwae Pharma Corporation
• Inventors: Ha, JongRyul, Kim, DaeHoon, Oh, SeWoong, Kahn, Michael, Hojjati-Emami, Katayoon
• Granted Patent: US 7,531,320 B2
• Time in Patent Office: Days
• US Class Current: 514/44.R
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/5025 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07K 14/47 from mammals
• CPC Class Codes: C12Q 1/02 involving viable microorganisms
• CPC Class Codes: C12Q 1/18 Testing for antimicrobial activity of a material
• CPC Class Codes: G01N 2333/37 from fungi

Abstract

The present invention provides compounds and methods for modulating transcription activated by β-catenin/TCF, such as the selective inhibition of genes targeted by the Wnt/β-catenin pathway.

Claims

1. A method for modulating the expression of a target gene induced by β

-catenin comprising contacting a composition with an agent, where the composition comprises β

-catenin, CBP and p300, where β

-catenin has a likelihood of binding to CBP versus p300, and the agent is contacted with the composition in an amount effective to change the likelihood of β

-catenin binding to CBP versus p300.

2. The method of claim 1 wherein the agent increases the binding of CBP to β

-catenin.

3. The method of claim 2 wherein the agent decreases the binding of p300 to β

-catenin.

4. The method of claim 1 wherein the agent increases the binding of p300 to β

-catenin.

5. The method of claim 4 wherein the agent decreases the binding of CBP to β

-catenin.

6. The method of claim 1 wherein the composition is ex vivo.

7. The method of claim 6 wherein the composition comprises a stem cell.

8. The method of claim 1 wherein the composition is a cell or a mammal.

9. The method of claim 8 wherein the mammal suffers from cancer, and the amount is effective to treat the cancer.

10. The method of claim 9 wherein the cancer is colon caner.

11. The method of claim 9 wherein the cancer is selected from prostate and breast cancer.

12. The method of claim 1 wherein the composition is a cell, and the agent increases the likelihood that the cell will differentiate rather than proliferate.

13. The method of claim 1 wherein the composition is a cell, and the agent increases the likelihood that the cell will proliferate rather than differentiate.

14. The method of claim 1 wherein the agent has a structure selected from formula (I):

15. The method of claim 14, wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are independently selected from the group consisting of aminoC_2-5alkyl, guanidinoC_2-5alkyl, C_1-4alkylguanidinoC_2-5alkyl, diC_1-4alkylguanidino-C_2-5alkyl, amidinoC_2-5alkyl, C_1-4alkylamidinoC_2-5alkyl, diC_1-4alkylamidinoC_2-5alkyl, C_1-3alkoxy, phenyl, substituted phenyl(where the substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C_1-4alkylamino, C_1-4dialkylamino, halogen, perfluoro C_1-4alkyl, C_1-4alkyl, C_1-3alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), benzyl, substituted benzyl (where the substituents on the benzyl are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C_1-4alkylamino, C_1-4dialkylamino, halogen, perfluoro C_1-4alkyl, C_1-3alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), naphthyl, substituted naphthyl (where the substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C_1-4alkylamino, C_1-4dialkylamino, halogen, perfluoro C_1-4alkyl, C_1-4alkyl, C_1-3alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), bis-phenyl methyl, substituted bis-phenyl methyl (where the substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C_1-4alkylamino, C_1-4dialkylamino, halogen, perfluoro C_1-4alkyl, C_1-4alkyl, C_1-3alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), pyridyl, substituted pyridyl, (where the substituents are independently selected from one or more of amino amidino, guanidino, hydrazino, amidazonyl, C_1-4alkylamino, C_1-4dialkylamino, halogen, perfluoro C_1-4alkyl, C_1-4alkyl, C_1-3alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), pyridylC_1-4alkyl, substituted pyridylC_1-4alkyl (where the pyridine substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C_1-4alkylamino, C_1-4dialkylamino, halogen, perfluoro C_1-4alkyl, C_1-4alkyl, C_1-3alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), pyrimidylC_1-4alkyl, substituted pyrimidylC_1-4alkyl (where the pyrimidine substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C_1-4alkylamino, C_1-4dialkylamino, halogen, perfluoro C_1-4alkyl, C_1-4alkyl, C_1-3alkoxy or nitro, carboxy, cyano, sulfuryl or hydroxyl), triazin-2-yl-C_1-4alkyl, substituted triazin-2-yl-C_1-4alkyl (where the triazine substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C_1-4alkylamino, C_1-4dialkylamino, halogen, perfluoro C_1-4alkyl, C_1-4alkyl, C_1-3alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), imidazoC_1-4alkyl, substituted imidazol C_1-4alkl (where the imidazole sustituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C_1-4alkylamino, C_1-4dialkylamino, halogen, perfluoro C_1-4alkyl, C_1-4alkyl, C_1-3alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), imidazolinylC_1-4alkyl, N-amidinopiperazinyl-N—

C_0-4alkyl, hydroxyC_2-5alkyl, C_1-5alkylaminoC_2-5alkyl, hydroxyC_2-5alkyl, C_1-5alkylaminoC_2-5alkyl, C_1-5dialkylaminoC_2-5alkyl, N-amidinopiperidinylC_1-4alkyl and 4-aminocyclohexylC_0-2alkyl.

16. The method of claim 14, wherein A is —

(CHR₃)—

, B is —

(C═

O)—

, D is CHR₅)—

, E is —

(C═

O)—

, G is —

(XR₇)_n—

, and the compound has the following general formula (II);

17. The method of claim 14, wherein A is —

(C═

O)—

, B is —

(CHR₄)—

, D is —

(C═

O)—

, E is —

(ZR₆)—

, G is —

(C═

O)—

(XR₉)—

, and the compound has the following general formula (III);

18. The compound of claim 14, wherein A is —

(C═

O)—

, B is —

(CHR₄)—

, D is —

(C═

O)—

, E is —

(ZR₆)—

, G is (XR₇)_n—

, and the compound has the following general formula (IV);

19. The method of claim 18, wherein the compound has the following general formula (VI):

20. The method of claim 19, wherein R_a is naphthyl, quinolinyl or isoquinolinyl group, and R_b is phenyl, pyridyl or piperidyl, all of which may be substituted with one or more substituents selected from a group consisting of halide, hydroxy, cyano, lower alkyl, and lower alkoxy group.

21. The method of claim 20, wherein R_a is naphthyl, and R_b is phenyl, which may be substituted with one or more substituents selected from a group consisting of halide, hydroxy, cyano, lower alkyl, and lower alkoxy group.

22. The method of claim 14 wherein the agent is COMPOUND1.

23. A composition comprising an agent, β

-catenin, CBP and p300, where β

-catenin has a likelihood of binding to CBP versus p300, and the agent is present in the composition in an amount effective to change the likelihood of β

-catenin binding to CBP versus p300.

24. The composition of claim 23 wherein the agent increases the binding of CBP to β

-catenin.

25. The composition of claim 24 wherein the agent decreases the binding of p300 to β

-catenin.

26. The composition of claim 23 wherein the agent increases the binding of p300 to β

-catenin.

27. The composition of claim 26 wherein the agent decreases the binding of CBP to β

-catenin.

28. The composition of claim 23 in an ex vivo state.

29. The composition of claim 28 further comprising a stem cell.

30. The composition of claim 29 wherein the agent increases the likelihood that the cell will differentiate rather than proliferate.

31. The composition of claim 29 wherein the agent increases the likelihood that the cell will proliferate rather than differentiate.

32. The composition of claim 23 wherein the agent has a structure selected from formula (I):

33. The compound of claim 32 wherein the agent is COMPOUND1.

34. A method for modulating the activity of the Wnt pathway comprising

(a) contacting (i) a composition comprising the components of the Wnt pathway with (ii) a compound that activates the Wnt pathway, to provide activated Wnt pathway;

and

(b) modulating the activity of the Wnt pathway with a chemical agent that completely or substantially interferes with binding between p300 and β

-catenin but causes little or no interference with binding between CBP and β

-catenin.

35. The method of claim 34 wherein the composition is a cell.

36. The method of claim 34 performed ex vivo.

37. The method of claim 34 wherein the compound is LiCl or a GSK3 inhibitor.

38. The method of claim 34 wherein the chemical agent has a structure selected from formula (I):

39. A method for modulating cell proliferation comprising:

(a) providing a cell population under conditions where a proportion of the population will proliferate and a proportion of the population will differentiate; and

(b) adding a chemical agent to the population, where the agent causes an increase in the proportion of the cells that proliferate relative to the proportion of the cells that differentiate.

40. The method of claim 39 wherein the compound interferes with binding between p300 and β

-catenin.

41. The method of claim 39 further comprising adding an agent to the population that activates a Wnt pathway.

42. The method of claim 39 wherein the cell population is a population of stem cells.

43. The method of claim 39 performed ex vivo.

44. The method of claim 39 further comprising adding an agent that causes differentiation of the cell population.

45. The method of claim 44 wherein cells in the population differentiate to form blood cells.

46. The method of claim 44 wherein cells in the population differentiate to form neuron cells, muscle cells, bone cells, or pancreatic beta-cells.

47. The method of claim 44 wherein the chemical agent has a structure selected from formula (I):

48. A method for selectively inhibiting β

-catenin/CBP interaction relative to β

-catenin/p300 interaction, the method comprising administering a compound to a composition, where the composition comprises β

-catenin, CBP and p300, and the compound selectively inhibits β

-catenin/CBP interaction relative to β

-catenin/p300 interacts.

49. The method of claim 48 wherein the compound has a structure selected from formula (I):

50. A method for selectively inhibiting β

-catenin/p300 interaction relative to β

-catenin/CBP interaction, the method comprising administering a compound to a composition, where the composition comprises β

-catenin, CBP and p300, and the compound selectively inhibits β

-catenin/p300 interaction relative to β

-catenin/CBP interacts.

51. The method of claim 50 wherein the compound has a structure selected from formula (I):

52. A method for enhancing translocation of β

-catenin from the nucleus to the cytosol, the method comprising administering a compound to a cell, where the cell comprises a nucleus and a cytosol, and the nucleus contains β

-catenin, and the compound causes translocation of β

-catenin from the nucleus to the cytosol.

53. The method of claim 52 wherein the compound has a structure selected from formula (I):

54. A method for selectively inhibiting expression of genes targeted by the WNT/β

-catenin pathway, the method comprising administering a compound to a composition, the composition comprising genes targeted by the WNT/β

-catenin pathway, the compound causing a change in expression of the genes targeted by the WNT/β

-catenin pathway.

55. The method of claim 54 wherein the compound has a structure selected from formula (I):

56. A method for maintaining a stem cell in an undifferentiated state, comprising contacting the stem cell with an agent that inhibits cell differentiation or promotes cell proliferation in an amount effective to maintain the stem cell in an undifferentiated state.

57. The method according to claim 56 wherein the agent selectively inhibits β

-catenin/p300 interaction relative to β

-catenin/CBP interaction.

58. A method for identifying a small molecule inhibitor of the β

-catenin;

CBP interaction comprising the steps of;

(a) contacting a putative beta-catenin;

CBP small molecule inhibitor with a moiety comprising CBP 1-111;

(b) contacting the admixture of step (a) with a moiety comprising β

-catenin;

(c) determining, by assay means, if said molecule of step (a) inhibits the binding of the moiety comprising β

-catenin of step (b) with the moiety comprising CBP 1-111 of step (a); and

(d) identifying, upon determination that said small molecule of step (a) inhibits the binding of said moiety comprising CBP 1-111 with the moiety comprising β

-catenin, the small molecule of step (a) as an inhibitor of beta-catenin;

CBP interaction.

59. The method of claim 58 further comprising the steps of:

(e) contacting the identified small molecule inhibitor of β

-catenin;

CBP interaction of step (d) with an admixture comprising (1) a moiety comprising p300 1-111 and (2) β

-catenin;

(f) determining, by assay means, if said molecule of step (e) does not inhibit the binding of said moiety comprising p300 1-111 with β

-catenin; and

(g) confirming, upon determination that said small molecule of step (e) does not inhibit the binding of said moiety comprising p300 1-111 with said β

-catenin, that said small molecule is a selective inhibitor of β

-catenin;

CBP interaction.

60. A method for identifying a small molecule inhibitor of the β

-catenin;

CBP interaction comprising the steps of;

(a) contacting a putative β

-catenin;

CBP small molecule inhibitor with a moiety comprising β

-catenin;

(b) contacting the admixture of step (a) with a moiety comprising CBP 1-111;

(c) determining, by assay means, if said molecule of step (a) inhibits the binding of the moiety comprising CBP 1-111 of step (b) with the moiety comprising β

-catenin of step (a);

(d) identifying, upon determination that said small molecule of step (a) inhibits the binding of said moiety comprising β

-catenin with the moiety comprising CBP 1-111, the small molecule of step (a) as an inhibitor of β

-catenin;

CBP interaction.

61. The method of claim 60 further comprising the steps of:

(e) contacting the identified small molecule inhibitor of β

-catenin;

CBP interaction of step (d) with an admixture comprising (1) a moiety comprising p300 1-111 and (2) β

-catenin;

(f) determining, by assay means, if said molecule of step (e) does not inhibit the binding of said moiety comprising p300 1-111 with β

-catenin; and

(g) confirming, upon determination that said small molecule of step (e) does not inhibit the binding of said moiety comprising p300 1-111 with said β

-catenin, that said small molecule is a selective inhibitor of β

-catenin;

CBP interaction.

62. A method for identifying a small molecule inhibitor of the β

-catenin;

CBP interaction comprising the steps of;

(a) contacting a putative beta-catenin;

CBP small molecule inhibitor with a moiety, said moiety comprising (1) β

-catenin associated with CBP 1-111;

(b) determining, by assay means, if said molecule of step (a) disassociates CBP 1-110 from β

-catenin; and

(c) identifying, upon determination that said small molecule of step (a) disassociates the binding of β

-catenin from CBP 1-111, the small molecule of step (a) as an inhibitor of β

-catenin;

CBP interaction.

63. The method of claim 62 further comprising the steps of:

(d) contacting the identified small molecule inhibitor of β

-catenin;

CBP interaction of step (c) with an admixture comprising (1) a moiety comprising p300 1-111 and (2) β

-catenin;

(e) determining, by assay means, if said molecule of step (d) does not inhibit the binding of said moiety comprising p300 1-111 with β

-catenin; and

(f) confirming, upon determination that said small molecule of step (d) does not inhibit the binding of said moiety comprising p300 1-111 with said β

-catenin, that said small molecule is a selective inhibitor of β

-catenin;

CBP interaction.

64. A method for identifying a small molecule inhibitor of the β

-catenin;

p300 interaction comprising the steps of;

(a) contacting a putative beta-catenin;

CBP small molecule inhibitor with a moiety comprising p300 1-111;

(b) contacting the admixture of step (a) with a moiety comprising β

-catenin;

(c) determining, by assay means, if said molecule of step (a) inhibits the binding of the moiety comprising β

-catenin of step (b) with the moiety comprising p300 1-111 of step (a); and

(d) identifying, upon determination that said small molecule of step (a) inhibits the binding of said moiety comprising p300 1-111 with the moiety comprising β

-catenin, the small molecule of step (a) as an inhibitor of beta-catenin;

p300 interaction.

65. The method of claim 64 further comprising the steps of:

(e) contacting the identified small molecule inhibitor of β

-catenin;

p300 interaction of step (d) with an admixture comprising (1) a moiety comprising CBP 1-111 and (2) β

-catenin;

(f) determining, by assay means, if said molecule of step (e) does not inhibit the binding of said moiety comprising CBP 1-111 with β

-catenin; and

(g) confirming, upon determination that said small molecule of step (e) does not inhibit the binding of said moiety comprising CBP 1-111 with said β

-catenin, that said small molecule is a selective inhibitor of β

-catenin;

p300 interaction.

66. A method for identifying a small molecule inhibitor of the β

-catenin;

p300 interaction comprising the steps of;

(a) contacting a putative β

-catenin;

p300 small molecule inhibitor with a moiety comprising β

-catenin;

(b) contacting the admixture of step (a) with a moiety comprising p300 1-111;

(c) determining, by assay means, if said molecule of step (a) inhibits the binding of the moiety comprising p300 1-111 of step (b) with the moiety comprising β

-catenin of step (a);

(d) identifying, upon determination that said small molecule of step (a) inhibits the binding of said moiety comprising β

-catenin with the moiety comprising p300 1-111, the small molecule of step (a) as an inhibitor of β

-catenin;

p300 interaction.

67. The method of claim 66 further comprising the steps of:

(e) contacting the identified small molecule inhibitor of β

-catenin;

p300 interaction of step (d) with an admixture comprising (1) a moiety comprising CBP 1-111 and (2) β

-catenin;

(f) determining, by assay means, if said molecule of step (e) does not inhibit the binding of said moiety comprising CBP 1-111 with β

-catenin; and

(g) confirming, upon determination that said small molecule of step (e) does not inhibit the binding of said moiety comprising CBP 1-111 with said β

-catenin, that said small molecule is a selective inhibitor of β

-catenin;

p300 interaction.

68. A method for identifying a small molecule inhibitor of the β

-catenin;

p300 interaction comprising the steps of;

(a) contacting a putative beta-catenin;

p300 small molecule inhibitor with a moiety, said moiety comprising (1) β

-catenin associated with p300 1-111;

(b) determining, by assay means, if said molecule of step (a) disassociates p300 1-111 from β

-catenin; and

(c) identifying, upon determination that said small molecule of step (a) disassociates the binding of β

-catenin from p300 1-111, the small molecule of step (a) as an inhibitor of β

-catenin;

p300 interaction.

69. The method of claim 68 further comprising the steps of:

(d) contacting the identified small molecule inhibitor of β

-catenin;

p300 interaction of step (c) with an admixture comprising (1) a moiety comprising CBP 1-111 and (2) β

-catenin;

(e) determining, by assay means, if said molecule of step (d) does not inhibit the binding of said moiety comprising CBP 1-111 with β

-catenin; and

(f) confirming, upon determination that said small molecule of step (d) does not inhibit the binding of said moiety comprising CBP 1-111 with said β

-catenin, that said small molecule is a selective inhibitor of β

-catenin;

p300 interaction.

70. A substantially purified and isolated nucleic acid molecule comprising SEQ ID NO:

1 or a sequence having at least 80% identity to SEQ ID NO;

1, with the proviso that said sequence does not encode a full-length CBP protein.

71. The nucleic acid molecule according to claim 70 comprising a nucleotide sequence having at least 90% identity to SEQ ID NO:

1.

72. The nucleic acid molecule according to claim 70 encoding a peptide that binds to β

-catenin.

73. The nucleic acid molecule according to claim 70 encoding a peptide that contains no more than 200 consecutive amino acid residues present within a CBP protein.

74. The nucleic acid molecule according to claim 70 encoding a peptide that contains no more than 150 consecutive amino acid residues present within a CBP protein.

75. The nucleic acid molecule according to claim 74 wherein the peptide comprises SEQ ID NO:

2 or SEQ ID NO;

5.

76. A substantially purified and isolated nucleic acid molecule comprising a fragment of SEQ ID NO:

1 or a sequence having at least 80% identity to said fragment, with the proviso that said sequence does not encode a full-length CBP protein.

77. The nucleic acid molecule according to claim 76 wherein said fragment has 90-300 nucleic acids.

78. The nucleic acid molecule according to claim 76 having at least 90% identity to said fragment.

79. The nucleic acid molecule according to claim 76 wherein said fragment encodes a peptide that binds to β

-catenin.

80. A substantially purified and isolated peptide comprising SEQ ID NO:

2 or a peptide having at least 80% identity to SEQ ID NO;

2, with the proviso that said peptide is not a full-length CBP protein.

81. The peptide according to claim 80 having at least 90% identity to SEQ ID NO:

2.

82. The peptide according to claim 80 that binds to β

-catenin.

83. The peptide according to claim 80 containing no more than 200 consecutive amino acid residues present within a CBP protein.

84. The peptide according to claim 80 containing no more than 150 consecutive amino acid residues present within a CBP protein.

85. The peptide according to claim 84 comprising SEQ ID NO:

2 or 4.

86. A substantially purified and isolated peptide comprising a fragment of SEQ ID NO:

2 or a sequence having at least 80% identity to said fragment, with the proviso that peptide is not a full-length CBP protein.

87. The peptide of claim 86 wherein said fragment has 30-100 amino acids.

88. The peptide of claim 86 having at least 90% identity to said fragment.

89. The peptide of claim 86 wherein said peptide binds to β

-catenin.

90. A substantially purified and isolated nucleic acid molecule consisting essentially of SEQ ID NO:

1 or a sequence having at least 80% identity to SEQ ID NO;

1, with the proviso that said sequence does not encode a full length CBP protein.

91. The nucleic acid molecule according to claim 90 having at least 90% identity to SEQ ID NO:

1.

92. The nucleic acid molecule according to claim 90 that encodes a peptide that binds to β

-catenin.

93. A substantially purified and isolated nucleic acid molecule consisting essentially of a fragment of SEQ ID NO:

1 or a sequence having at least 80% identity to said fragment.

94. The nucleic acid molecule according to claim 93 wherein said fragment has 90-300 nucleotides.

95. The nucleic acid molecule according to claim 93 having at least 90% identity to said fragment.

96. The nucleic acid molecule according to claim 93 wherein said fragment encodes a peptide that binds to β

-catenin.

97. A substantially purified and isolated peptide consisting essentially of SEQ ID NO:

2 or a peptide having at least 80% identity to SEQ ID NO;

2.

98. The peptide of claim 97 having at least 90% identity to SEQ ID NO:

2.

99. The peptide of claim 97 that binds to β

-catenin.

100. A substantially purified and isolated peptide consisting essentially of a fragment of SEQ ID NO:

2 or a sequence having at least 80% identity to said fragment.

101. The peptide of claim 100 wherein said fragment has 30-100 amino acids.

102. The peptide of claim 100 having at least 90% identity to said fragment.

103. The peptide of claim 100 wherein said peptide binds to β

-catenin.

104. A substantially purified and isolated nucleic acid molecule consisting of SEQ ID NO:

1 or a sequence having at least 80% identity to SEQ ID NO;

1.

105. The nucleic acid molecule of claim 104 having at least 90% identity to SEQ ID NO:

1.

106. The nucleic acid molecule of claim 104 that encodes a peptide that binds to β

-catenin.

107. A substantially purified and isolated nucleic acid molecule consisting of a fragment of SEQ ID NO:

1 or a sequence having at least 80% identity to said fragment.

108. The nucleic acid molecule of claim 107 wherein said fragment has 90-300 nucleotides.

109. The nucleic acid molecule of claim 107 having at least 90% identity to said fragment.

110. The nucleic acid molecule of claim 107 wherein said fragment encodes a peptide that binds to β

-catenin.

111. A substantially purified and isolated peptide consisting of SEQ ID NO:

2 or a peptide having at least 80% identity to SEQ ID NO;

2.

112. The peptide of claim 111 having at least 90% identity to SEQ ID NO:

2.

113. The peptide of claim 111 that binds to β

-catenin.

114. A substantially purified and isolated peptide consisting of a fragment of SEQ ID NO:

2 or a sequence having at least 80% identity to said fragment.

115. The peptide of claim 114 wherein said fragment has 30-100 amino acids.

116. The peptide of claim 114 having at least 90% identity to said fragment.

117. The peptide of claim 114 wherein said peptide binds to β

-catenin.

118. A substantially purified and isolated nucleic acid molecule comprising SEQ ID NO:

3 or a sequence having at least 80% identity to SEQ ID NO;

3, with the proviso that said sequence does not encode a full-length p300 protein.

119. The nucleic acid molecule of claim 118 having at least 90% identity to SEQ ID NO:

3.

120. The nucleic acid molecule of claim 118 that encodes a peptide that binds to β

-catenin.

121. The nucleic acid molecule of claim 118 encoding a peptide that contains no more than 200 consecutive amino acid residues present within a p300 protein.

122. The nucleic acid molecule of claim 118 encoding a peptide that contains no more than 150 consecutive amino acid residues present within a p300 protein.

123. The nucleic acid molecule of claim 122 wherein the peptide comprises SEQ ID NO:

4.

124. A substantially purified and isolated nucleic acid molecule comprising a fragment of SEQ ID NO:

3 or a sequence having at least 80% identity to said fragment, with the proviso that said sequence does not encode a full-length p300 protein.

125. The nucleic acid molecule of claim 124 wherein said fragment has 90-300 nucleotides.

126. The nucleic acid molecule of claim 124 having at least 90% identity to said fragment.

127. The nucleic acid molecule of claim 124 wherein said fragment encodes a peptide that binds to β

-catenin.

128. A substantially purified and isolated peptide comprising SEQ ID NO:

4 or a peptide having at least 80% identity to SEQ ID NO;

4, with the proviso that said peptide is not a full-length p300 protein.

129. The peptide of claim 128 having at least 90% identity to SEQ ID NO:

4.

130. The peptide of claim 128 that binds to β

-catenin.

131. The peptide of claim 128 containing no more than 200 consecutive amino acid residues present within a p300 protein.

132. The peptide of claim 128 containing no more than 150 consecutive amino acid residues present within a p300 protein.

133. The peptide of claim 132 comprising SEQ ID NO:

4.

134. A substantially purified and isolated peptide comprising a fragment of SEQ ID NO:

4 or a sequence having at least 80% identity to said fragment, with the proviso that peptide is not a full-length p300 protein.

135. The peptide of claim 134 wherein said fragment has 30-100 amino acids.

136. The peptide of claim 134 having at least 90% identity to said fragment.

137. The peptide of claim 134 wherein said peptide binds to β

-catenin.

138. A substantially purified and isolated nucleic acid molecule consisting essentially of SEQ ID NO:

3 or a sequence having at least 80% identity to SEQ ID NO;

3.

139. The nucleic acid molecule of claim 138 having at least 90% identity to SEQ ID NO:

3.

140. The nucleic acid molecule of claim 138 encoding a peptide that binds to β

-catenin.

141. A substantially purified and isolated nucleic acid molecule consisting essentially of a fragment of SEQ ID NO:

3 or a sequence having at least 80% identity to said fragment.

142. The nucleic acid molecule of claim 141 wherein said fragment has 90-300 nucleotides.

143. The nucleic acid molecule of claim 141 having at least 90% identity to said fragment.

144. The nucleic acid molecule of claim 141 wherein said fragment encodes a peptide that binds to β

-catenin.

145. A substantially purified and isolated peptide consisting essentially of SEQ ID NO:

4 or a peptide having at least 80% identity to SEQ ID NO;

4.

146. The peptide of claim 145 having at least 90% identity to SEQ ID NO:

4.

147. The peptide of claim 145 that binds to β

-catenin.

148. A substantially purified and isolated peptide consisting essentially of a fragment of SEQ ID NO:

4 or a sequence having at least 80% identity to said fragment.

149. The peptide of claim 148 wherein said fragment has 30-100 amino acids.

150. The peptide of claim 148 having at least 90% identity to said fragment.

151. The peptide of claim 148 wherein said peptide binds to β

-catenin.

152. A substantially purified and isolated nucleic acid molecule consisting of SEQ ID NO:

3 or a sequence having at least 80% identity to SEQ ID NO;

3.

153. The nucleic acid molecule of claim 152 having at least 90% identity to SEQ ID NO:

3.

154. The nucleic acid molecule of claim 152 that encodes a peptide that binds to β

-catenin.

155. A substantially purified and isolated nucleic acid molecule consisting of a fragment of SEQ ID NO:

3 or a sequence having at least 80% identity to said fragment.

156. The nucleic acid molecule of claim 155 wherein said fragment has 90-300 nucleotides.

157. The nucleic acid molecule of claim 155 having at least 90% identity to said fragment.

158. The nucleic acid molecule of claim 155 wherein said fragment encodes a peptide that binds to β

-catenin.

159. A substantially purified and isolated peptide consisting of SEQ ID NO:

4 or a peptide having at least 80% identity to SEQ ID NO;

4.

160. The peptide of claim 159 having at least 90% identity to SEQ ID NO:

4.

161. The peptide of claim 159 that binds to β

-catenin.

162. A substantially purified and isolated peptide consisting of a fragment of SEQ ID NO:

4 or a sequence having at least 80% identity to said fragment.

163. The peptide of claim 162 wherein said fragment has 30-100 amino acids.

164. The peptide of claim 162 having at least 90% identity to said fragment.

165. The peptide of claim 162 wherein said peptide binds to β

-catenin.