Peptide inhibitors of BCR-ABL oligomerization
In one aspect, the invention relates to peptides comprising the Bcr-Abl coiled-coil oligomerization domain and an alpha helix stabilizing moiety, mutant forms thereof, truncated forms thereof, derivatives thereof, and related peptides, which are useful as inhibitors of the Bcr-Abl chimeric protein; pharmaceutical compositions comprising the compounds; and methods of treating hyperproliferative disorders associated with Bcr-Abl using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
1. A peptide comprising,
a Bcr-Abl coiled-coil oligomerization domain comprising the sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6;
wherein a pair of amino acids are modified to be α,α-disubstituted amino acids, wherein at least one of the amino acids in the pair is at position 29, 30, 33, 36, 37, 40, 43, 44, 47, 50, 51, 54, 57, 58, 61, 64 or 65 of the sequence of SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:3 or at position 2, 3, 6, 9, 10, 13, 16, 17, 20, 23, 24, 27, 30, 31, 34, 37, 38 of the sequence of SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6, wherein the pair of amino acids are in the i, i+3; i, i+4; or i, i+7 configuration;
wherein the Bcr-Abl coiled-coil oligomerization domain comprises at least one alpha helix stabilizing moiety.
2. A peptide comprising,
a Bcr-Abl coiled-coil oligomerization domain, wherein the Bcr-Abl coiled-coil oligomerization domain comprises the sequence of VGDIEQELERAEARIRRDEQRVNQERFRMIYLETLLAKEK (amino acids 28-67 of SEQ ID NO:7);
wherein a pair of amino acids are modified to be α,α-disubstituted amino acids, wherein at least one of the amino acids in the pair is at position 2, 3, 6, 9, 10, 13, 16, 17, 20, 23, 24, 27, 30, 31, 34, 37, 38 of the sequence VGDIEQELERAEARIRRDEQRVNQERFRMIYLETLLAKEK, wherein the pair of amino acids are in the i+3; i, i+4; or i, i+7 configuration;
wherein the Bcr-Abl inhibitory activity of the Bcr-Abl coiled-coil oligomerization domain comprising the sequence of VGDIEQELERAEARIRRDEQRVNQERFRMIYLETLLAKEK (amino acids 28-67 of SEQ ID NO:7) is greater than that of SEQ ID NO:1; and
wherein the Bcr-Abl coiled-coil oligomerization domain comprises at least one alpha helix stabilizing moiety.
3. A peptide comprising,
a Bcr-Abl coiled-coil oligomerization domain, wherein the Bcr-Abl coiled-coil oligomerization domain comprises the sequence of SEQ ID NO:8;
wherein a pair of amino acids are modified to be α,α-disubstituted amino acids, wherein at least one of the amino acids in the pair is at position 2, 3, 7, 10, 11, 14, 17, 18, 21, 24, 25, 28, 31, 32, 35, 38, 39 of the sequence SEQ ID NO:8, wherein the pair of amino acids are in the i, i+i, i+4; or i, i+7 configuration;
wherein one or more amino acid(s) of the Bcr-Abl coiled-coil oligomerization domain designated by X in SEQ ID NO:8 is an amino acid different from the corresponding amino acid of SEQ ID NO:4;
wherein the Bcr-Abl inhibitory activity of the Bcr-Abl coiled-coil oligomerization domain comprising the sequence of SEQ ID NO:8 is greater than that of SEQ ID NO:4; and
wherein the Bcr-Abl coiled-coil oligomerization domain comprises at least one alpha helix stabilizing moiety.
4. A method of treating a Bcr-Abl inhibitor responsive hyperproliferative disorder in a mammal, comprising the step of administering to the mammal an effective amount of at least one peptide of claim 1 .
5. A method of inhibiting Bcr-Abl activity in a mammal, comprising the step of administering to the mammal an effective amount of at least one peptide of claim 1 .
6. The method of claim 5 , further comprising a pharmaceutically acceptable salt or solvate of the peptide.
7. The method of claim 5 , wherein the peptide comprises a cell-penetrating peptide.
8. The method of claim 5 , wherein the mammal is human.
9. The method of claim 5 , wherein the mammal has been diagnosed with a need for inhibiting Bcr-Abl activity prior to the administering step.
10. The method of claim 5 , further comprising the step of identifying a mammal in need of inhibiting Bcr-Abl activity.
11. A method of inhibiting Bcr-Abl activity in at least one cell, comprising the step of contacting the cell with an effective amount of at least one peptide of claim 1 .
12. A method of treating Bcr-Abl inhibitor responsive hyperproliferative disorder in a mammal, comprising the step of administering to the mammal an effective amount of at least one peptide of claim 2 .
13. A method of treating a Bcr-Abl inhibitor responsive hyperproliferative disorder in a mammal, comprising the step of administering to the mammal an effective amount of at least one peptide of claim 3 .
14. A method of inhibiting Bcr-Abl activity in a mammal, comprising the step of administering to the mammal an effective amount of at least one peptide of claim 2 .
15. A method of inhibiting Bcr-Abl activity in a mammal, comprising the step of administering to the mammal an effective amount of at least one peptide of claim 3 .
16. A method of inhibiting Bcr-Abl activity in at least one cell, comprising the step of contacting the cell with an effective amount of at least one peptide of claim 2 .
17. A method of inhibiting Bcr-Abl activity in at least one cell, comprising the step of contacting the cell with an effective amount of at least one peptide of claim 3 .
18. The peptide of any one of claims 1 , 2 , and 3 , wherein the at least one alpha helix stabilizing moiety is a hydrocarbon staple, an acetylenic crosslink, a lactam bridge, or a combination thereof.
19. The peptide of claim 1 , wherein each α,α-disubstituted amino acid is a α-methyl,α-alkenylglycine or α-hydro,α-alkenylglycine residue having the structure:
wherein n is an integer between 1 and 10, inclusive; and wherein R b is H or methyl.
20. The peptide of claim 2 , wherein each α,α-disubstituted amino acid is a α-methyl,α-alkenylglycine or α-hydro,α-alkenylglycine residue having the structure:
wherein n is an integer between 1 and 10, inclusive; and wherein R b is H or methyl.
21. The peptide of claim 3 , wherein each α,α-disubstituted amino acid is a α-methyl,α-alkenylglycine or α-hydro,α-alkenylglycine residue having the structure:
wherein n is an integer between 1 and 10, inclusive; and wherein R b is H or methyl.