Activation of peptide prodrugs by hK2
The invention provides novel peptide prodrugs that contain cleavage sites specifically cleaved by human kallikrein 2 (hK2). These prodrugs are useful for substantially inhibiting the non-specific toxicity of a variety of therapeutic drugs. Upon cleavage of the prodrug by hK2, the therapeutic drugs are activated and exert their toxicity. Methods for treating cell proliferative disorders are also featured in the invention.
1. A composition comprising a prodrug, the prodrug comprising:
a therapeutically active drug; wherein the therapeutic active drug is not an amino acid or peptide; and
the peptide consisting of the sequence GKAFRR (SEQ ID NO:9),
wherein the peptide is linked to the therapeutically active drug to inhibit the therapeutic activity of the drug, and
wherein the therapeutically active drug is cleaved from the peptide upon proteolysis by an enzyme having a proteolytic activity of human kallikrein 2 (hk2).
2. The composition of claim 1 , wherein the peptide is linked directly to a primary amine group on the drug.
3. The composition of claim 1 , wherein the therapeutically active drug inhibits a SERCA pump.
4. The composition of claim 1 , wherein the therapeutically active drug is selected from the group consisting of primary amine containing thapsigargins and thapsigargin derivatives.
5. The composition of claim 4 , wherein the thapsigargin derivative is 8-O-(12-[L-leucinoylamino]dodecanoyl)-8-O-debutanoylthapsigargin (L12ADT).
6. The composition of claim 1 , wherein the therapeutically active drug intercalates into a polynucleotide.
7. The composition of claim 6 , wherein the therapeutically active drug is an anthracycline.
8. The composition of claim 7 , wherein the anthracycline is selected from the group consisting of doxorubicin, daunorubicin, epirubicin, and idarubicin.
9. The composition of claim 1 , wherein the therapeutically active drug is a taxane.
10. The composition of claim 9 , wherein the taxane is selected from the group consisting of paclitaxel and docetaxel.
11. The composition of claim 1 , wherein the therapeutically active drug is a vinca alkaloid.
12. The composition of claim 11 , wherein the vinca alkaloid is selected from the group consisting of vincristine, vinblastine, and etoposide.
13. The composition of claim 1 , wherein the therapeutically active drug is an antiandrogen.
14. The composition of claim 13 , wherein the antiandrogen is selected from the group consisting of biscalutamide, flutamide, nilutamide, and cyproterone acetate.
15. The composition of claim 1 , wherein the therapeutically active drug is an antifolate.
16. The composition of claim 15 , wherein the antifolate is methotrexate.
17. The composition of claim 1 , wherein the therapeutically active drug is a nucleoside analog.
18. The composition of claim 17 , wherein the nucleoside analog is selected from the group consisting of 5-Fluorouracil, gemcitabine, and 5-azacytidine.
19. The composition of claim 1 , wherein the therapeutically active drug is a topoisomerase inhibitor.
20. The composition of claim 19 , wherein the topoisomerase inhibitor is selected from the group consisting of Topotecan and irinotecan.
21. The composition of claim 1 , wherein the therapeutically active drug is an alkylating agent.
22. The composition of claim 21 , wherein the alkylating agent is selected from the group consisting of cyclophosphamide, cisplatinum, carboplatinum, and ifosfamide.
23. The composition of claim 1 , wherein the therapeutically active drug is a targeted radiation sensitizer.
24. The composition of claim 23 , wherein the targeted radiation sensitizer is selected from the group consisting of 5-fluorouracil, gemcitabine, topoisomerase inhibitors, and cisplatinum.
25. The composition of claim 1 , wherein the therapeutically active drug has an IC 50 toward ER Ca 2+ -ATPase of at most 500 nM.
26. The composition of claim 1 , wherein the therapeutically active drug has an IC 50 toward ER Ca 2+ -ATPase of at most 50 nM.
27. The composition of claim 1 , wherein the therapeutically active drug has an LC 50 toward hK2-producing tissue of at most 20 μM.
28. The composition of claim 1 , wherein the therapeutically active drug has an LC 50 toward hK2-producing tissue of less than or equal to 2.0 μM.