Methods of treating cancer using compounds containing a vascular disrupting agent
The present invention relates to prodrugs of vascular disrupting agents comprising a vascular disrupting agent (VDA) associated with a MMP proteolytic cleavage site and to the use of such prodrugs in the targeted treatment of cancer.
1. A peptide comprising the amino acid sequence -Arg-Ser-Cit-Gly-Hof-P2′-Leu-, wherein P2′ is an amino acid, provided that P2′ is not tyrosine.
2. The peptide according to claim 1 , wherein P2′ is selected from the group consisting of Asp, Ala, Ser, Asn, Pro, Leu, Arg and Thr.
3. The peptide according to claim 1 , further comprising a capping group c at the N- or C-terminus of the peptide.
4. The peptide according to claim 3 , wherein c is selected from fluorescein, fluorescein derivatives, simple sugars, D-amino acids or proline imino acids.
5. A prodrug comprising
a biologically active compound associated with
a peptide comprising a matrix metalloproteinase (MMP) proteolytic cleavage site comprising the amino acid sequence -Arg-Ser-Cit-Gly-Hof-P2′-Leu-, wherein P2′ is an amino acid, provided that P2′ is not tyrosine.
6. The prodrug according to claim 5 , wherein P2′ is selected from the group consisting of Asp, Ala, Ser, Asn, Pro, Leu, Arg and Thr.
7. The prodrug according to claim 5 , wherein the biologically active compound is an anti-tumour agent or a vascular disrupting agent (VDA).
8. The prodrug according to claim 5 , wherein the peptide has a capping group c to prevent non-specific degradation of the peptide.
9. The prodrug according to claim 8 , wherein c is selected from fluorescein, fluorescein derivatives, simple sugars, D-amino acids or proline imino acids.
10. A compound of
X-Y-c, formula (II):
or
X-a-Y-c, formula (IV):
or
X-Y-b-c, formula (V):
or
X-a-Y-b-c, formula (VI):
wherein:
Y is a peptide comprising the amino acid sequence -Arg-Ser-Cit-Gly-Hof-P2′-Leu-, wherein P2′ is an amino acid, provided that P2′ is not tyrosine,
c is a capping group,
a is a linker,
b is a spacer, and
X is an anticancer agent.
11. The compound according to claim 10 , wherein P2′ is selected from the group consisting of Asp, Ala, Ser, Asn, Pro, Leu, Arg and Thr.
12. The compound according to claim 10 , wherein c is selected from fluorescein, fluorescein derivatives, simple sugars, D-amino acids or proline imino acids.
13. The compound of claim 10 , wherein the anti-cancer agent is a vascular disrupting agent (VDA).
14. The compound of claim 10 , wherein the linker is a single amino acid or an amino acid sequence.
15. A method of producing a systemically deactivated and MMP overexpression site activatable medicament, the method comprising attaching to the medicament a peptide comprising an MMP proteolytic cleavage site comprising the amino acid sequence -Arg-Ser-Cit-Gly-Hof-P2′-Leu-, wherein P2′ is an amino acid, and provided that P2′ is not tyrosine.
16. The method according to claim 15 , wherein P2′ is selected from the group consisting of Asp, Ala, Ser, Asn, Pro, Leu, Arg and Thr.
17. A method of modifying a drug to overcome a toxic effect of systemic administration of the drug, comprising associating the drug with a peptide comprising a MMP proteolytic cleavage site -Arg-Ser-Cit-Gly-Hof-P2′-Leu-, wherein P2′ is an amino acid, provided that P2′ is not tyrosine, and wherein the peptide has a capping group c on the N- or C-terminus to prevent non-specific degradation of the peptide.
18. The method according to claim 17 , wherein P2′ is selected from the group consisting of Asp, Ala, Ser, Asn, Pro, Leu, Arg and Thr.
19. The method according to claim 17 , wherein c is selected from fluorescein, fluorescein derivatives, simple sugars, D-amino acids or proline imino acids.
20. A method of increasing the therapeutic index of a drug, the method comprising associating the drug with a peptide comprising -Arg-Ser-Cit-Gly-Hof-P2′-Leu-, wherein P2′ is an amino acid, provided that P2′ is not tyrosine, and having wherein the peptide has a capping group c on the N- or C-terminus, thereby reducing systemic levels of active drug and increasing the therapeutic index.
21. The method according to claim 20 , wherein P2′ is selected from the group consisting of Asp, Ala, Ser, Asn, Pro, Leu, Arg and Thr.
22. The method according to claim 20 , wherein c is selected from fluorescein, fluorescein derivatives, simple sugars, D-amino acids or proline imino acids.
23. A method of modifying a drug, the method comprising associating the drug with a peptide comprising a MMP proteolytic cleavage site -Arg-Ser-Cit-Gly-Hof-P2′-Leu-, wherein P2′ is an amino acid, provided that P2′ is not tyrosine, and wherein the peptide has a capping group c on the N- or C-terminus to prevent non-specific degradation of the peptide.
24. The method according to claim 23 , wherein P2′ is selected from the group consisting of Asp, Ala, Ser, Asn, Pro, Leu, Arg and Thr.
25. The method according to claim 23 , wherein c is selected from fluorescein, fluorescein derivatives, simple sugars, D-amino acids or proline imino acids.