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 method of treating prostate cancer, the method comprising
administering to a subject in need thereof a therapeutically effective amount of a prodrug comprising
a therapeutically active drug comprising the thapsigargin derivative 8-O-(12-[L-leucinoylamino]dodecanoyl)-8-O-debutanoylthapsigargin (L12ADT) and a peptide comprising an amino acid sequence having a cleavage site specific for an enzyme having a proteolytic activity of hK2,
wherein the peptide is linked to the therapeutically active drug to inhibit the therapeutic activity of the drug, and
wherein the peptide consists of the amino acid sequence G-K-A-F-R-R (SEQ ID NO: 9), and
wherein the therapeutically active drug is cleaved from the peptide upon proteolysis by an enzyme having a proteolytic activity of hK2.
2. The method of claim 1 , wherein the peptide is linked directly to the therapeutic drug.
3. The method of claim 2 , wherein the pepetide is linked directly to a primary amine group on the therapeutic drug.
4. The method of claim 1 , wherein the peptide is linked to the therapeutic drug via a linker.
5. The method of claim 4 , wherein the linker is an amino acid sequence.
6. The method of claim 5 , wherein the linker comprises a leucine residue.
7. The method of claim 4 , wherein the linker is selected from the group consisting of:
(a) CO—(CH═CH) n1 —(CH 2 ) n2 —Ar—NH 2 ,
(b) CO—(CH 2 ) n2 —(CH═CH) n1 —Ar—NH 2 ,
(c) CO—(CH 2 ) n2 —(CH═CH) n1 —CO—NH—Ar—NH 2 ,
(d) CO—(CH═CH) n1 —(CH 2 ) n2 —CO—NH—Ar—NH 2 ,
(e) CO—(CH 2 ) n3 —NH 2 , and
(f) CO—(CH 2 ) n3 —NH—CO—CH(R 4 )—NH 2 ,
each of which is unsubstituted or alkyl-, aryl-, halo-, alkoxy-, alkenyl-, amido- or amino-substituted, and wherein n1 and n2 are from 0 to 5, n3 is from 0 to 15, Ar is any substituted or unsubstituted aryl group, attachment of NH 2 to Ar is in a ortho, meta or para position with respect to the remainder of the linker, and R 4 is any naturally occurring amino acid side chain.