FAP-activated proteasome inhibitors for treating solid tumors
Disclosed are proteasome inhibitors, fibroblast activation protein (FAP)-activated prodrugs of proteasome inhibitors, and pharmaceutically acceptable salts of the inhibitors and prodrugs. Also disclosed are related pharmaceutical compositions, and methods of using the inhibitors and prodrugs and compositions thereof, for example, in treating cancer or other cell proliferative diseases. In vitro and in vivo methods of quantifying the expression of FAP in a biopsy sample and a mammal, respectively, are also disclosed.
1. A method of inhibiting proteasome function in a cell, comprising contacting the cell with an effective amount of a fibroblast activation protein (FAP)-activated proteasome inhibitor represented by formula III:
wherein
R 1 —(C═O)— represents an acyl N-terminal blocking group;
R 2 represents H, lower alkyl, or a mono- or di-hydroxy-substituted lower alkyl;
R 3 represents lower alkyl;
R 4 is absent;
R 5 represents a hydrophobic amino acid sidechain;
R 6 represents alkyl, cycloalkyl, aryl, heterocycle or —(CH 2 ) n —R 7 ;
R 7 represents aryl, aralkyl, cycloalkyl, alkoxy, alkylthio, —OH or —SH;
R 11 represents H or lower alkyl;
W represents
Y 1 and Y 2 are independently OH, or a group capable of being hydrolyzed to a hydroxyl group; or Y 1 and Y 2 taken together with the B to which they are attached form a ring having from 5 to 8 atoms in the ring structure; and
n is an integer in the range of 1 to 8.
2. The method of claim 1 , wherein R 3 is methyl.
3. The method of claim 1 , wherein Y 1 and Y 2 are OH.
4. The method of claim 1 , wherein R 6 is iso-butyl.
5. The method of claim 4 , wherein R 11 is H.
6. The method of claim 1 , wherein the FAP-activated proteasome inhibitor is represented by:
7. A method of inhibiting antigen presentation in a cell, comprising contacting the cell with an effective amount of a fibroblast activation protein (FAP)-activated proteasome inhibitor represented by formula III:
wherein
R 1 —(C═O)— represents an acyl N-terminal blocking group;
R 2 represents H, lower alkyl, or a mono- or di-hydroxy-substituted lower alkyl;
R 3 represents lower alkyl;
R 4 is absent;
R 5 represents a hydrophobic amino acid sidechain;
R 6 represents alkyl, cycloalkyl, aryl, heterocycle or —(CH 2 ) n —R 7 ;
R 7 represents aryl, aralkyl, cycloalkyl, alkoxy, alkylthio, —OH or —SH;
R 11 represents H or lower alkyl;
W represents
Y 1 and Y 2 are independently OH, or a group capable of being hydrolyzed to a hydroxyl group; or Y 1 and Y 2 taken together with the B to which they are attached form a ring having from 5 to 8 atoms in the ring structure; and
n is an integer in the range of 1 to 8.
8. The method of claim 7 , wherein R 3 is methyl.
9. The method of claim 7 , wherein Y 1 and Y 2 are OH.
10. The method of claim 7 , wherein R 6 is iso-butyl.
11. The method of claim 7 , wherein R 11 is H.
12. The method of claim 7 , wherein the FAP-activated proteasome inhibitor is represented by:
13. A method of inhibiting HIV infection in a mammal, comprising administering to a mammal in need thereof a therapeutically effective amount of a fibroblast activation protein (FAP)-activated proteasome inhibitor represented by formula III:
wherein
R 1 —(C═O)— represents an acyl N-terminal blocking group;
R 2 represents H, lower alkyl, or a mono- or di-hydroxy-substituted lower alkyl;
R 3 represents lower alkyl;
R 4 is absent;
R 5 represents a hydrophobic amino acid sidechain;
R 6 represents alkyl, cycloalkyl, aryl, heterocycle or —(CH 2 ) n —R 7 ;
R 7 represents aryl, aralkyl, cycloalkyl, alkoxy, alkylthio, —OH or —SH;
R 11 represents H or lower alkyl;
W represents
Y 1 and Y 2 are independently OH, or a group capable of being hydrolyzed to a hydroxyl group; or Y 1 and Y 2 taken together with the B to which they are attached form a ring having from 5 to 8 atoms in the ring structure; and
n is an integer in the range of 1 to 8.
14. The method of claim 13 , wherein R 3 is methyl.
15. The method of claim 13 , wherein Y 1 and Y 2 are OH.
16. The method of claim 13 , wherein R 6 is iso-butyl.
17. The method of claim 13 , wherein R 11 is H.
18. The method of claim 13 , wherein the FAP-activated proteasome inhibitor is represented by: