FAP-activated therapeutic agents, and uses related thereto
Disclosed are prodrugs of anthracyclines (such as doxorubicin) and derivatives thereof that are selectively cleaved and activated by fibroblast activating protein (FAP). The prodrugs are useful for targeted delivery of “warhead” anthracycline or anthracycline derivative to FAP-expressing tissues, including cancer (e.g., solid tumors). Also provided are pharmaceutical compositions comprising the prodrugs, as well as methods of using the prodrugs to treat a disorder characterized by FAP upregulation, e.g., cancer, undesirable fibrosis, and undesirable inflammation.
1. A prodrug represented by Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 represents (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkyl-C(O)—(C 1 -C 10 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 10 )alkyl, aryl, aryl(C 1 -C 10 )alkyl, heteroaryl, or heteroaryl(C 1 -C 10 )alkyl, wherein any R 1 is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, carboxylate, cyano, amino, nitro, and thio (—SH); or
represents an N-terminally blocked alpha amino acid residue, wherein X is O;
R 2 represents H or a (C 1 -C 6 )alkyl;
R 3 represents a (C 1 -C 6 )alkyl;
R 4 is absent or represents a (C 1 -C 6 )alkyl, —OH, —NH 2 , or halogen;
X represents O or S;
L represents a bond, or
represents a self-immolative linker; and
Cyt′ represents a radical of an anthracycline or derivative thereof.
2. The prodrug of claim 1 , wherein L is a bond.
3. The prodrug of claim 1 , wherein the anthracycline or derivative thereof is doxorubicin.
4. The prodrug of claim 1 , wherein L is a self-immolative linker.
5. The prodrug of claim 4 , wherein the anthracycline or derivative thereof is doxorubicin.
6. The prodrug of claim 1 , wherein R 2 is H.
7. The prodrug of claim 1 , wherein R 3 is methyl, ethyl, propyl, or isopropyl.
8. The prodrug of claim 1 , wherein R 3 is methyl.
9. The prodrug of claim 1 , wherein
represents an N-terminally blocked alpha amino acid residue, wherein X is O, which comprises a moiety which, at physiological pH, reduces cell permeability of the prodrug relative to the anthracycline or derivative thereof.
10. The prodrug of claim 1 , wherein
represents an N-terminally blocked alpha amino acid residue, wherein X is O, which comprises one or more functional groups that are ionized at physiological pH.
11. The prodrug of claim 1 , wherein
represents an N-terminally blocked alpha amino acid residue, wherein X is O, and the terminal blocking group is an acyl(C 1 -C 10 )alkyl substituted with one or more functional groups that are ionized at physiological pH.
12. The prodrug of claim 11 , wherein
represents an N-terminally blocked alpha amino acid residue, wherein X is O, and the terminal blocking group is represented by the formula HO 2 C—(C 1 -C 10 )alkyl-C(O)—.
13. The prodrug of claim 11 , wherein
represents an N-terminally blocked alpha amino acid residue, wherein X is O, and the terminal blocking group is represented by the formula HO 2 C—(CH 2 ) 2 —C(O)—.
14. The prodrug of claim 1 , wherein
represents an N-terminally blocked alpha amino acid residue, wherein X is O, and the terminal blocking group is selected from the group consisting of formyl, dansyl, acetyl, benzoyl, trifluoroacetyl, succinyl, and methoxysuccinyl.
15. The prodrug of claim 1 , wherein
represents an N-terminally blocked alpha amino acid residue, wherein X is O, and the terminal blocking group is selected from the group consisting of aryl(C 1 -C 6 )acyl and heteroaryl(C 1 -C 6 )acyl.
16. The prodrug of claim 15 , wherein
represents an N-terminally blocked alpha amino acid residue, wherein X is O, and the terminal blocking group is an aryl(C 1 -C 6 )acyl.
17. The prodrug of claim 16 , wherein the aryl(C 1 -C 6 )acyl is a (C 1 -C 6 )acyl substituted with an aryl selected from the group consisting of benzyl, naphthalenyl, phenanthrenyl, phenolyl, and anilinyl.
18. The prodrug of claim 17 , wherein the aryl(C 1 -C 6 )acyl is a (C 1 )acyl substituted with an aryl selected from the group consisting of benzyl, naphthalenyl, phenanthrenyl, phenolyl, and anilinyl.
19. The prodrug of claim 15 , wherein
represents an N-terminally blocked alpha amino acid residue, wherein X is O, and R 1 is a heteroaryl(C 1 -C 6 )acyl.
20. The prodrug of claim 19 , wherein the heteroaryl(C 1 -C 6 )acyl is a (C 1 -C 6 )acyl substituted with a heteroaryl selected from the group consisting of pyrryl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl.
21. The prodrug of claim 20 , wherein the heteroaryl(C 1 -C 6 )acyl is a (C 1 )acyl substituted with a heteroaryl selected from the group consisting of pyrryl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl.
22. The prodrug of claim 1 , represented by the formula
23. A pharmaceutical composition, comprising a prodrug of claim 1 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
24. A method of treating a disorder in which fibroblast activation protein (FAP) is upregulated, comprising administering to a subject in need thereof a therapeutically effective amount of a prodrug of claim 1 , or a pharmaceutically acceptable salt thereof.
25. The method of claim 24 , wherein the disorder is selected from the group consisting of cancer, fibrosis, and inflammation.
26. The method of claim 24 , wherein the disorder is cancer.
27. The method of claim 24 , wherein the disorder is fibrosis.
28. The method of claim 24 , wherein the disorder is inflammation.
29. The prodrug of claim 1 , wherein X is O, and
is acyl(C 1 -C 10 )alkyl substituted with one or more functional groups that are ionized at physiological pH.
30. The prodrug of claim 1 , wherein X is O, and
is HO 2 C—(C 1 -C 10 )alkyl-C(O)—.
31. The prodrug of claim 1 , wherein X is O, and
is HO 2 C—(CH 2 ) 2 —C(O)—.
32. The prodrug of claim 1 , wherein X is O, and
is selected from the group consisting of formyl, dansyl, acetyl, benzoyl, trifluoroacetyl, succinyl, and methoxysuccinyl.
33. The prodrug of claim 1 , wherein X is O, and
is selected from the group consisting of aryl(C 1 -C 6 )acyl and heteroaryl(C 1 -C 6 )acyl.
34. The prodrug of claim 33 , wherein X is O, and
is aryl(C 1 -C 6 )acyl.
35. The prodrug of claim 34 , wherein aryl(C 1 -C 6 )acyl is a (C 1 -C 6 )acyl substituted with an aryl selected from the group consisting of benzyl, naphthalenyl, phenanthrenyl, phenolyl, and anilinyl.
36. The prodrug of claim 35 , wherein aryl(C 1 -C 6 )acyl is a (C 1 )acyl substituted with an aryl selected from the group consisting of benzyl, naphthalenyl, phenanthrenyl, phenolyl, and anilinyl.
37. The prodrug of claim 33 , wherein X is O, and
is heteroaryl(C 1 -C 6 )acyl.
38. The prodrug of claim 37 , wherein heteroaryl(C 1 -C 6 )acyl is a (C 1 -C 6 )acyl substituted with a heteroaryl selected from the group consisting of pyrryl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl.
39. The prodrug of claim 38 , wherein heteroaryl(C 1 -C 6 )acyl is a (C 1 )acyl substituted with a heteroaryl selected from the group consisting of pyrryl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl.