Methods of treating cancer using compounds containing a vascular disrupting agent
Inventors
Falconer, Robert Andrew • Gill, Jason • Xavier, Jennifer • Loadman, Paul • Bibby, Michael • Patterson, Laurence
Assignees
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Publication Number
US-9937267-B2
Publication Date
2018-04-10
Expiration Date
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.
Core Innovation
The disclosure provides prodrugs comprising a vascular disrupting agent (VDA) associated with a matrix metalloproteinase (MMP) proteolytic cleavage site so that the VDA is released upon proteolytic cleavage. The VDA is selected from specified tubulin-binding vascular disrupting agents and other listed VDAs, and the associated cleavage site is designed as a peptide cleavage motif included within the compound architecture.
A key element is a defined MMP proteolytic cleavage site amino acid sequence, including an -Leu-P2′-Hof-Gly-Cit-Ser-Arg- motif where P2′ is selected from a restricted set of amino acids. The disclosure also describes peptide cleavage-site design rules using a peptide sequence Y linked via an X—Y relationship, together with linker/spacer elements and an optional capping group (c).
The disclosure further describes optional compound architecture elements including labeled core compound formulae (I–IX) that capture the arrangement of the VDA, the MMP-cleavable peptide sequence, optional capping group, linker/spacer, and related end-cap concepts. It also describes the potential inclusion of a second anti-cancer agent (Z), including doxorubicin, as part of combination therapy or as an additional conjugated therapeutic element.
Claims Coverage
The independent claim coverage centers on treatment of solid tumors using a compound that combines a vascular disrupting agent (VDA) with a matrix metalloproteinase (MMP) proteolytic cleavage site, where the cleavage site includes a defined amino acid motif with a restricted P2′ residue set. Dependent features further describe compound architecture, VDA selection, peptide sequence limits, optional capping group, and optional combination therapy.
Solid tumor treatment via VDA–MMP proteolytic cleavage site compound
A method of treating a solid tumor in a subject comprising administering an effective amount of a compound comprising a vascular disrupting agent (VDA) associated with a matrix metalloproteinase (MMP) proteolytic cleavage site.
Defined VDA selection for the prodrug
The VDA is selected from the group consisting of azademethylcolchicine, colchicine, azacolchicine, N-methyl desacetylcolchicine, desacetylcolchicine, N-acetylcolchinol-O-phosphate, colchicinoids, combrestatins, phenstatin, podophyllotoxins, steganacins, amphethinile, stilbenes, flavonoids, vincristine, vinblastine, vinflunine, maytansinoids, phomopson A, rhizoxin, auristatin, and dolstatin.
Leu-P2′-Hof-Gly-Cit-Ser-Arg MMP cleavage site with restricted P2′
The MMP proteolytic cleavage site comprises the amino acid sequence -Leu-P2′-Hof-Gly-Cit-Ser-Arg-, wherein P2′ is an amino acid selected from Asp, Ala, Ser, Asn, Pro, Leu, Arg and Thr.
Peptide length and capping group architecture
Dependent features describe peptide sequence Y consisting of between seven and ten amino acids and an optional capping group that prevents non-specific degradation by enzymes other than MMPs.
Combination therapy with a second therapeutic agent
The pharmaceutical formulation includes a second therapeutic agent selected from the specified list, including doxorubicin, as part of combination therapy or an additional conjugated therapeutic element.
Overall, the claim coverage is centered on administering a VDA prodrug activated by an MMP proteolytic cleavage site defined by a specific peptide motif and a restricted P2′ amino acid set, with additional features directed to compound format, peptide length, capping group, and combination therapy.
Stated Advantages
Improved tumor-to-normal activation selectivity for MMP-activated prodrugs.
Documented Applications
Treating solid tumors in a subject using a compound comprising a VDA associated with an MMP proteolytic cleavage site.
Tumor activation studies showing VDA2 formation in tumor after cleavage at the Gly-Hof motif and low or undetectable VDA2 in normal tissues after 24 h.
Ex vivo and in vivo assessment of selective cleavage and activation for an MT-MMP/MT1-MMP selective prodrug versus a pan-MMP prodrug.
Tumor efficacy evaluation in HT1080 xenograft mice.
Solubility and stability evaluation across modified approaches, including modified or glycosylated amino-acid side chains and P2′ substitutions.
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