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 compounds 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 method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of 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 3 )cycloalkyl, (C 3 -C 3 )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 —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 one, two, or three substituents, each independently selected from the group consisting of (C 1 -C 6 )alkyl, —OH, —NH 2 , and halogen;
X represents O or S;
L represents a bond, or —N(H)-L- represents a self-immolative linker; and
Cyt′ represents a radical of an anthracycline or derivative thereof.
2 . The method of claim 1 , wherein L is a bond.
3 . The method of claim 1 , wherein the anthracycline or derivative thereof is doxorubicin.
4 . The method of claim 1 , wherein —N(H)-L-represents a self-immolative linker.
5 . (canceled)
6 . The method of claim 1 , wherein R 2 is H.
7 . (canceled)
8 . The method of claim 1 , wherein R 3 is methyl, ethyl, propyl, or isopropyl.
9 . The method of claim 1 , wherein R 3 is methyl.
10 . The method of claim 1 , wherein
is a moiety which, at physiological pH, reduces cell permeability of the compound relative to the anthracycline or derivative thereof.
11 . The method of claim 1 , wherein
comprises one or more functional groups that are ionized at physiological pH.
12 . (canceled)
13 . The method of claim 1 , wherein
is represented by the formula HO 2 C—(C 1 -C 10 )alkyl-C(O)—.
14 . (canceled)
15 . (canceled)
16 . The method of claim 1 , wherein
is selected from the group consisting of aryl(C 1 -C 6 )acyl and heteroaryl(C 1 -C 6 )acyl.
17 - 22 . (canceled)
23 . The method of claim 1 , wherein —C(X)R 1 represents an N-terminally blocked alpha amino acid residue, wherein X is O.
24 . The method of claim 1 , wherein the compound is represented by a formula selected from the group consisting of:
25 . The method of claim 1 , wherein the compound is represented by the formula
or a pharmaceutically acceptable salt thereof.
26 - 36 . (canceled)
37 . The method of claim 1 , wherein R 4 is absent or represents two halogens.
38 . The method of claim 1 , 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 3 )cycloalkyl, (C 3 -C 3 )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 —SH; or
represents an N-terminally blocked alpha amino acid residue;
R 2 represents H;
R 3 represents a (C 1 -C 6 )alkyl;
R 4 is absent or represents two halogens;
X represents O;
L represents a bond, or —N(H)-L- represents a self-immolative linker; and
Cyt′ represents a radical of doxorubicin.
39 . The method of claim 1 , wherein:
R 1 represents a heteroaryl that is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, carboxylate, cyano, amino, nitro, and —SH;
R 2 represents H;
R 3 represents a (C 1 -C 6 )alkyl;
R 4 is absent or represents two halogens;
X represents O;
L represents a bond, or —N(H)-L- represents a self-immolative linker; and
Cyt′ represents a radical of doxorubicin.
40 . The method of claim 1 , wherein the cancer is soft tissue sarcoma, breast carcinoma, non-small cell lung carcinoma, or colorectal carcinoma.
41 . The method of claim 1 , wherein the cancer is breast carcinoma.
42 . The method of claim 1 , wherein the cancer is soft tissue sarcoma.
43 . The method of claim 25 , wherein the cancer is soft tissue sarcoma, breast carcinoma, non-small cell lung carcinoma, or colorectal carcinoma.
44 . The method of claim 25 , wherein the cancer is breast carcinoma.
45 . The method of claim 25 , wherein the cancer is soft tissue sarcoma.