Compounds containing a vascular disrupting agent
The present invention relates to compounds, and pharmaceutically acceptable salts thereof, comprising a vascular disrupting agent (VDA) associated and a MMP proteolytic cleavage site. The compounds are useful in the treatment of cancer.
1. A compound or pharmaceutically acceptable salt thereof, comprising a compound X which promotes the formation of stable microtubules in a manner similar to paclitaxel associated with a peptide Y comprising a matrix metalloproteinase cleavage site comprising the amino acid sequence -Arg-Ser-Cit-Gly-Hof-Tyr-Leu- (SEQ ID NO: 4).
2. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound X is a taxane.
3. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound X is paclitaxel.
4. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound X which promotes the formation of stable microtubules in a manner similar to paclitaxel is linked directly or indirectly to the peptide.
5. The compound or pharmaceutically acceptable salt thereof according to claim 1 , further comprising a linker a directly or indirectly associated with X.
6. The compound or pharmaceutically acceptable salt thereof according to claim 5 , wherein the linker a is on the C terminus of the amino acid sequence Y.
7. The compound or pharmaceutically acceptable salt thereof according to claim 5 or 6 , wherein the linker a may be removed chemically, enzymatically or decompose spontaneously.
8. The compound or pharmaceutically acceptable salt thereof according to claim 1 , further comprising a capping group c to prevent non-specific degradation of the peptide.
9. The compound or pharmaceutically acceptable salt thereof according to claim 8 , wherein the capping group c is on the N terminus of the peptide.
10. The compound or pharmaceutically acceptable salt thereof according to claim 8 , wherein the capping group c is selected from simple sugars, D-amino acids, proline imino acids, fluorescein, and fluorescein derivatives.
11. The compound or pharmaceutically acceptable salt thereof according to claim 1 , further comprising a spacer b directly or indirectly associated with the peptide Y.
12. The compound or pharmaceutically acceptable salt thereof according to claim 11 , wherein the spacer b is on the N terminus of the peptide Y.
13. The compound or pharmaceutically acceptable salt thereof according to claim 11 , wherein the spacer is selected from a single amino acid, an amino acid sequence and a succinyl group.
14. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound has formula (VI):
X-a-Y-b-c (VI)
and each of X, a, Y, b and c are defines as follows:
X is a taxane,
a is a linker directly or indirectly associated with X,
Y is a peptide comprising a matrix metalloproteinase cleavage site comprising the amino acid sequence -Arg-Ser-Cit-Gly-Hof-Tyr-Leu- (SEQ ID NO: 4),
b is a spacer directly or indirectly associated with the peptide Y, and
c is a capping group to prevent non-specific degradation of the peptide.
15. A compound or pharmaceutically acceptable salt thereof, comprising paclitaxel conjugated via a linker to a peptide comprising a MMP proteolytic cleavage site and comprising the amino acid sequence -Arg-Ser-Cit-Gly-Hof-Tyr-Leu- (SEQ ID NO: 4).
16. A pharmaceutical formulation comprising a compound or pharmaceutically acceptable salt thereof according to claim 1 or 15 and at least one pharmaceutically acceptable excipient, diluent or carrier.
17. A pharmaceutical formulation according to claim 16 , further comprising another anticancer agent.
18. A method of treating cancer in a subject comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt thereof according to claim 15 .
19. A method of treating cancer in a subject comprising administering to the subject an effective amount of compound or pharmaceutically acceptable salt thereof according to claim 1 .
20. The method according to claim 18 or 19 , wherein the cancer is prostate cancer.
21. A method of treating cancer in a subject comprising administering to the subject an effective amount of a pharmaceutical formulation comprising a compound according to claim 1 .
22. The method according to claim 21 , wherein the cancer is prostate cancer.
23. The compound of claim 10 wherein the fluorescein derivative is fluorescein isothiocycante (FITC).
24. The compound of claim 13 wherein the single amino acid is β-alanine.