Targeted delivery to legumain-expressing cells
The present invention relates to new agents and methods useful for preventing, treating and diagnosing diseases such as cancer. For example, the invention relates to prodrug agents useful for targeting and delivering cytotoxic drugs to cancerous cells.
1. A prodrug compound, comprising cytosine arabinoside or doxorubicin linked to a legumain peptide substrate having a peptide consisting of amino acid sequence Ala-Ala-Asn-Leu (SEQ ID NO:5) and wherein legumain cleaves the peptide at the link between the Asn and another amino acid to generate active cytosine arabinoside or doxorubicin from the prodrug.
2. The compound of claim 1 , wherein the prodrug is substantially non-toxic to non-legumain expressing animal cells.
3. The compound of claim 1 , wherein the amino acid sequence comprises Boc-Ala-Ala-Asn-Leu (SEQ ID NO:4).
4. The compound of claim 1 , wherein the amino acid sequence comprises succinyl-Ala-Ala-Asn-Leu (SEQ ID NO:8).
5. The compound of claim 1 , wherein the peptide further comprises a protecting group.
6. The compound of claim 5 , wherein the protecting group is an amino protecting group.
7. The compound of claim 5 , wherein the protecting group is succinyl.
8. The compound of claim 5 , wherein the protecting group is t-butoxycarbonyl.
9. The compound of claim 5 , wherein the peptide further comprises an N-β-alanyl terminus.
10. A pharmaceutical composition, comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
11. A method for treating a mammal having cancer comprising administering to the mammal the compound of claim 1 in amounts and at intervals effective to reduce or eliminate one or more of the symptoms associated with cancer.
12. The method of claim 11 , wherein the cancer is a solid cancer.
13. The method of claim 11 , wherein the cancer is breast cancer, colon cancer, lung cancer, prostate cancer, ovarian cancer, cancer of the central nervous system, lymphoma, or melanoma.
14. The method of claim 11 , wherein the cancer is autoimmune deficiency syndrome-associated Kaposi's sarcoma, cancer of the adrenal cortex, cancer of the cervix, cancer of the endometrium, cancer of the esophagus, cancer of the head and neck, cancer of the liver, cancer of the pancreas, cancer of the prostate, cancer of the thymus, carcinoid tumors, chronic lymphocytic leukemia, Ewing's sarcoma, gestational trophoblastic tumors, hepatoblastoma, multiple myeloma, non-small cell lung cancer, retinoblastoma, or tumors in the ovaries.
15. A method for inhibiting metastasis of cancer in an animal, comprising administering the compound of claim 1 to the animal in amounts and at intervals effective to reduce or eliminate cancer metastasis.
16. A method for inhibiting cell migration in an animal, comprising administering the compound of claim 1 to the animal in amounts and at intervals effective to reduce or eliminate cancer cell migration.
17. A method of killing a cell in a tissue, comprising contacting the cell with the compound of claim 1 in amounts and at intervals effective to kill the cell, wherein the tissue comprises legumain.