Compounds containing a vascular disrupting agent

Inventors

Gill, Jason • Loadman, Paul • Falconer, Rob • Patterson, Laurence • Xavier, Jennifer • Bibby, Michael

Assignees

Ellipses Pharma Ltd

Abstract

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.

Core Innovation

The document describes VDA-associated prodrugs activated in vivo by MMP proteolytic cleavage at a peptide MMP proteolytic cleavage site comprising the amino acid sequence -Arg-Ser-Cit-Gly-Hof-Tyr-Leu- (SEQ ID NO: 4). The MMP proteolytic cleavage is directed to tumor environments using overexpressed MMPs, including MT-MMPs. The peptide cleavage motif is defined and incorporated into prodrug structures that carry a biologically active compound associated with the peptide.

The document further provides structural definitions for the VDA-associated prodrugs, including the peptide being associated with anticancer agents such as vascular disrupting agents and tubulin-binding VDAs. It describes optional capping, linker, and spacer moieties, where the capping group is used to prevent non-specific degradation of the peptide. The prodrug structures are expressed in multiple compound formats, with variables corresponding to anticancer agent, linker, spacer, and capping group.

The document also reports examples of specific conjugates, including colchicine-based constructs and a doxorubicin conjugate, along with ex vivo and in vivo findings. These findings include tumor-selective cleavage and stability in plasma/liver, and indicate higher tumor accumulation of the released VDA compared with normal tissues, as shown in FIGs. 1–6. Additional embodiments include pan-MMP versus MT-MMP selective prodrugs via cleavage-site residue substitutions and glycosylated amino-acid solubility enhancements.

Claims Coverage

The independent claims cover peptide sequences containing the specified MMP proteolytic cleavage site (SEQ ID NO: 4), prodrugs and anticancer-agent compounds incorporating that cleavage site with a capping group, and methods for producing and using systemically deactivated MMP-overexpression-site activatable medicaments and for modifying drugs to overcome toxic effects and increase the therapeutic index. Across these independent claims, the main inventive features are the specific cleavage-site peptide sequence (SEQ ID NO: 4) and the use of a terminal capping group on the peptide (N- or C-terminus) to prevent non-specific degradation, including defined compound formats and method outcomes.

Across the independent claims, coverage centers on the specified MMP proteolytic cleavage site peptide sequence (SEQ ID NO: 4) and its incorporation into peptide, prodrug, and anticancer-agent compound structures using a terminal capping group (N- or C-terminus) to prevent non-specific peptide degradation. The methods similarly rely on attaching or associating medicaments or drugs with the cleavage-site peptide to produce MMP-overexpression-site activatable medicaments, to overcome systemic toxicity, and to increase therapeutic index by reducing systemic levels of active drug.

Stated Advantages

Documented Applications