Cxcr4 antagonist and use thereof
The present invention provides preventive and/or therapeutic drugs for cancer and chronic rheumatoid arthritis which contain a peptide having a CXCR4 antagonism, its amide, its ester or its salt. Also, the present invention provides a novel peptide having a CXCR4 antagonism, its amide, its ester and its salt.
1. A peptide according to formula (I) Arg-Arg-Xaa 1 -Cys-Tyr-Xaa 2 -Lys-Xaa 3 -Pro-Tyr-Arg-Xaa 4 -Cys-Arg (I) (SEQ ID NO:64) or a salt thereof, wherein:
(a) each amino acid may be a D- or L-amino acid
(b) Xaa 1 is naphthylalanine;
(c) Xaa 2 and Xaa 4 are citrulline;
(d) Xaa 3 is Lys or D-Lys; and
(e) the Arg at position 1 is derivatized at the N-terminus with a substituted benzoyl group selected from the group consisting of 2-fluorobenzoyl, 3-fluorobenzoyl, 4-fluorobenzoyl, 2-bromobenzoyl, 3-bromobenzoyl, 4-bromobenzoyl, 2-nitrobenzoyl, 3-nitrobenzoyl and 4-nitrobenzoyl.
2. The peptide or salt of claim 1 wherein the substituted benzoyl group is a 4-fluorobenzoyl or 2-fluorobenzoyl group.
3. The peptide or salt of claim 2 wherein the substituted benzoyl group is a 4-fluorobenzoyl group.
4. The peptide or salt of claim 1 , wherein the Arg at position 14 is C-terminally amidated and Xaa 3 at position 8 is D-Lys.
5. The peptide or salt of claim 2 , wherein the Arg at position 14 is C-terminally amidated and Xaa 3 at position 8 is D-Lys.
6. The peptide or salt of claim 3 , wherein the Arg at position 14 is C-terminally amidated and Xaa 3 at position 8 is D-Lys.
7. A pharmaceutical composition comprising:
(a) the peptide or salt of claim 1 ; and
(b) a pharmaceutically acceptable carrier or excipient.
8. A pharmaceutical composition comprising:
(a) the peptide or salt of claim 2 ; and
(b) a pharmaceutically acceptable carrier or excipient.
9. A pharmaceutical composition comprising:
(a) the peptide or salt of claim 3 ; and
(b) a pharmaceutically acceptable carrier or excipient.
10. A pharmaceutical composition comprising:
(a) the peptide or salt of claim 4 ; and
(b) a pharmaceutically acceptable carrier or excipient.
11. A pharmaceutical composition comprising:
(a) the peptide or salt of claim 5 ; and
(b) a pharmaceutically acceptable carrier or excipient.
12. A pharmaceutical composition comprising:
(a) the peptide or salt of claim 6 ; and
(b) a pharmaceutically acceptable carrier or excipient.
13. A method for treating or ameliorating breast cancer, leukemia or chronic rheumatoid arthritis in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of the peptide or salt of claim 1 .
14. The method according to claim 13 for treating or ameliorating breast cancer.
15. The method of claim 14 , wherein the method inhibits breast cancer metastasis.
16. The method according to claim 13 , wherein said peptide or salt is a CXCR4 antagonist.
17. The method according to claim 13 , wherein the substituted benzoyl group of the peptide or salt is a 4-fluorobenzoyl or a 2-fluorobenzoyl group.
18. The method of claim 14 , wherein the substituted benzoyl group of the peptide or salt is a 4-fluorobenzoyl group or a 2-fluorobenzoyl group.
19. The method of claim 17 , wherein the substituted benzoyl group of the peptide or salt is a 4-fluorobenzoyl group.
20. The method of claim 13 wherein, in the peptide or salt, the Arg at position 14 is C-terminally amidated and Xaa 3 at position 8 is D-Lys.
21. The method of claim 14 wherein, in the peptide or salt, the Arg at position 14 is C-terminally amidated and Xaa 3 at position 8 is D-Lys.
22. The method of claim 17 wherein, in the peptide or salt, the Arg at position 14 is C-terminally amidated and Xaa 3 at position 8 is D-Lys.
23. The method of claim 19 wherein, in the peptide or salt, the Arg at position 14 is C-terminally amidated and Xaa 3 at position 8 is D-Lys.