Inhibiting tumor cell invasion, metastasis and angiogenesis
AssigneeThe Scripps Research Institute
InventorCheng Liu
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Abstract
The present invention relates to new compositions and methods useful for preventing, treating and diagnosing metastatic and/or invasive cancer and undesirable angiogenesis. For example, the invention relates to inhibitors of proteases that are specifically expressed in tumors, prodrugs activated in the tumor microenvironment and methods for using those inhibitors and prodrugs to inhibit angiogenesis and tumor cell invasion.
Claims35
A protease inhibitor consisting of any one of formulae III, IV, V or VI:
- R1-(Xaa4)n-Asn-Y
- (SEQ ID NO:26)
- III
- R1-(Xaa4)n-Xaa5-Y
- (SEQ ID NO:27)
- IV
- R1-Xaa4-azaAsn-Y
- V
- R1-Xaa4-azaXaa5-Y
- VI
- or a combination thereof, wherein:
- wherein R1 is hydrogen, a hydrophilic group, a hydrophobic group, a photosensitizing agent, a label or an amino protecting group;
- n is an integer of 2 to about 5;
- each Xaa4 and Xaa5 is an amino acid or an amino acid mimetic;
- Y is alkyl, alkenyl epoxide, fluoromethylketone or a Michael acceptor, optionally substituted with 1-3 halo or hydroxy, alkylamino, dialkylamino, alkyldialkylamino, or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, aryl;
- (C5-C12)arylalkyl or (C5-C12)arylalkenyl,
- wherein the aryl groups of the arylalky or arylalkenyl can be 0-4 heteroatoms selected from N, O and S, and are optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, —O—(C5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
- and
- wherein each of the inhibitors of formulae III, IV, V and VI bind to a protease expressed in a tumor microenvironment.
A prodrug with the structure:
- R1-peptide-drug
- wherein:
- R1 is hydrogen, a hydrophilic group, a hydrophobic group, a label or an amino protecting group;
- peptide is a peptidyl amino acid sequence that can be cleaved by a protease expressed by cells in a tumor;
- and
- drug is a therapeutic agent or toxin;
- wherein the drug is inactive until the peptide is cleaved by the protease.
An anti-legumain antibody that binds to an epitope consisting essentially of CGMKRASSPVPLPP (SEQ ID NO:
- 16).
Dependencies are inferred from the claim text.