Enzyme-activated anti-tumor prodrug compounds
View Patent ↗Disclosed are enzyme-activated anti-tumor and anti-metastatic prodrug compounds. The specific enzymes are collagenase(IV) and elastase. Also disclosed are methods of making and using such compounds.
1. A prodrug compound comprising:
a targeting-peptide chosen from SEQ ID NO:6 or SEQ ID NO:7, wherein the targeting-peptide has L or L and D amino acid residues and wherein the targeting-peptide is optionally covalently capped by a terminal amino capping group Z;
a linker group covalently attached to the targeting-peptide at the carboxy terminus; and
a cytotoxic drug covalently attached to the linker; wherein:
the targeting-peptide is an amino acid sequence which is catalytically cleaved by elastase;
the linker group is a bond or a self-immolating linker; and
Z is an amino protecting group chosen from tert-butyloxycarbonyl, benzyloxycarbonyl or an adhesion peptide; wherein there is an optional spacer molecule between Z and the targeting-peptide.
2. The prodrug compound according to claim 1 wherein the cytotoxic drug is selected from doxorubicin, mitomycin, paclitaxel, camptothecin, vincristine, vinblastine, fluorouracil, methotrexate, TNP-470, thalidomide and squalamine.
3. The prodrug compound according to claim 2 wherein the cytotoxic compound is doxorubicin.
4. The prodrug compound according to claim 3 wherein there is a spacer molecule between Z and the targeting-peptide.
5. The prodrug compound according to claim 4 wherein Z is an adhesion peptide selected from SEQ ID NO:3 and SEQ ID NO:4, wherein Z has L or L and D amino acid residues.
6. A pharmaceutical composition comprising a therapeutically effective amount of a prodrug compound according to claim 1 .