Agents modulating beta-catenin functions and methods thereof

1. A peptide comprising:

[X 1 ] p1 [X 2 ] p2 —X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 —[X 11 ] p11 [X 12 ] p12 [X 13 ] p13 ,

wherein:

each of p1, p2, p11, p12 and p13 is independently 0 or 1;

each of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , and X 13 is independently an amino acid residue;

at least two of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , and X 13 comprise side chains that are linked together to form a staple, wherein the peptide comprises a structure selected from:

wherein each X is independently an amino acid residue.

2. The peptide of claim 1 , wherein the peptide comprises

3. The peptide of claim 1 , wherein the peptide comprises

4. The peptide of claim 1 , wherein the peptide comprises

5. The peptide of claim 1 , wherein the peptide comprises

6. The peptide of claim 1 , wherein the peptide comprises

7. The peptide of claim 1 , wherein the peptide comprises

8. The peptide of claim 1 , wherein the peptide comprises

9. The peptide of claim 1 , wherein the peptide comprises

10. The peptide of claim 1 , wherein the peptide comprises

11. The peptide of claim 1 , wherein the peptide comprises one and no more than one staple.

12. The peptide of claim 1 , wherein the peptide comprises a structure selected from:

and wherein the peptide comprises two or more staples.

13. The peptide of claim 12 , wherein at least two staples are bonded to the same peptide backbone atom.

14. The peptide of claim 12 , wherein no two staples are bonded to the same peptide backbone atom.

15. A peptide comprising:

[X 1 ] p1 [X 2 ] p2 —X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 —[X 11 ] p11 [X 12 ] p12 [X 13 ] p13 ,

wherein:

each of p1, p2, p11, p12 and p13 is independently 0 or 1;

each of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , and X 13 is independently an amino acid residue;

at least two of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , and X 13 comprise side chains that are linked together to form a staple; and

the peptide comprises two or more staples, wherein the peptide comprises a structure selected from:

wherein each X is independently an amino acid residue.

16. The peptide of claim 15 , wherein at least two staples are bonded to the same peptide backbone atom.

17. The peptide of claim 15 , wherein no two staples are bonded to the same peptide backbone atom.

18. A peptide having the structure of:

or a salt thereof, wherein

each of R a , R 1 , R 2 , R 3 , and R 4 is independently R′;

R b is R′, —OR′ or —N(R′) 2 ;

each X is independently an amino acid residue;

a is 0-20;

each of b, c, s, and d is independently 1-20;

each of C 1 and C 2 is independently a carbon atom;

each L s is independently -L s1 -L s2 -L s3 -, wherein L s1 is bonded to C 1 and L s3 is bonded to C 2 ;

each of L s1 , L s2 , and L s3 is independently L;

each L is independently a covalent bond, or an optionally substituted, bivalent C 1 -C 20 aliphatic group wherein one or more methylene units of the aliphatic group are optionally and independently replaced with —C(R′) 2 —, -Cy-, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O) 2 —, —S(O) 2 N(R′)—, —C(O)S—, or —C(O)O—;

each -Cy- is independently an optionally substituted bivalent group selected from a C 3-20 cycloaliphatic ring, a C 6-20 aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;

each R′ is independently —R, —C(O)R, —CO 2 R, or —SO 2 R;

each R is independently —H, or an optionally substituted group selected from C 1-30 aliphatic, C 1-30 heteroaliphatic having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, C 6-30 aryl, C 6-30 arylaliphatic, C 6-30 arylheteroaliphatic having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or

two R groups are optionally and independently taken together to form a covalent bond, or:

two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or

two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;

wherein the peptide comprises two or more staples, wherein the peptide comprises a structure selected from:

19. A pharmaceutical composition comprising a peptide of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

20. A pharmaceutical composition comprising a peptide of claim 15 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

21. A pharmaceutical composition comprising a peptide of claim 18 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

22. The peptide of claim 1 , wherein the peptide comprises

23. The peptide of claim 1 , wherein the peptide comprises