Methods of treating cancer using compounds containing a vascular disrupting agent

Abstract

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.

What is claimed: 
     
         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-P2′-Leu- wherein P2′ is an amino acid. 
     
     
         2 . The compound or pharmaceutically acceptable salt thereof, according to  claim 1 , wherein P2′ is selected from the group consisting of Asp, Ala, Ser, Asn, Pro, Leu, Arg and Thr. 
     
     
         3 . The compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein the compound X is a taxane. 
     
     
         4 . The compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein the compound X is paclitaxel. 
     
     
         5 . 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. 
     
     
         6 . The compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein the MMP proteolytic cleavage site is a MMP-14 proteolytic cleavage site. 
     
     
         7 . The compound or pharmaceutically acceptable salt thereof according to  claim 1 , further comprising a linker a directly or indirectly associated with X. 
     
     
         8 . The compound or pharmaceutically acceptable salt thereof according to  claim 7 , wherein the linker a is on the C terminus of the amino acid sequence Y. 
     
     
         9 . The compound or pharmaceutically acceptable salt thereof according to  claim 7 , wherein the linker a may be removed chemically, enzymatically or decompose spontaneously. 
     
     
         10 . 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. 
     
     
         11 . The compound or pharmaceutically acceptable salt thereof according to  claim 10 , wherein the capping group c is on the N terminus of the peptide. 
     
     
         12 . The compound or pharmaceutically acceptable salt thereof according to  claim 10 , wherein the capping group c is selected from simple sugars, D-amino acids, proline imino acids, fluorescein, or fluorescein derivatives and preferably fluorescein isothiocycante (FITC). 
     
     
         13 . The compound or pharmaceutically acceptable salt thereof according to  claim 1 , further comprising a spacer b directly or indirectly associated with the peptide Y. 
     
     
         14 . The compound or pharmaceutically acceptable salt thereof according to  claim 13 , wherein the spacer b is on the N terminus of the peptide Y. 
     
     
         15 . The compound or pharmaceutically acceptable salt thereof according to  claim 13 , wherein the spacer is selected from a single amino acid and preferably β-alanine, an amino acid sequence or a succinyl group. 
     
     
         16 . The compound or pharmaceutically acceptable salt thereof according to preceding  claim 1 , wherein the compound has formula (VI):
   X-a-Y-b-c   (VI)
   
       and each of X, a, Y, b and c are as defined above. 
     
     
         17 . 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-P2′-Leu-, wherein P2′ is an amino acid. 
     
     
         18 . The compound or pharmaceutically acceptable salt thereof according to  claim 17 , wherein P2′ is selected from the group consisting of Asp, Ala, Ser, Asn, Pro, Leu, Arg and Thr. 
     
     
         19 . A pharmaceutical formulation comprising a compound or pharmaceutically acceptable salt thereof according to  claim 1  and at least one pharmaceutically acceptable excipient, diluent or carrier. 
     
     
         20 . A pharmaceutical formulation according to  claim 19 , further comprising another anticancer agent. 
     
     
         21 . A method of treating cancer, the method comprising administering a pharmaceutically effective amount of a compound or pharmaceutically acceptable salt thereof according to  claim 1  to a subject in need thereof. 
     
     
         22 . The method according to  claim 21 , wherein the cancer is prostate cancer. 
     
     
         23 . A method of treating cancer, the method comprising administering a pharmaceutical formulation according to  claim 19  to a subject in need thereof. 
     
     
         24 . The method of  claim 23 , wherein the cancer is prostate cancer.