FAP-activated proteasome inhibitors for treating solid tumors
AssigneeTrustees of Tufts College
InventorsWilliam W. Bachovchin, Hung-sen Lai, Sarah E. Poplawski
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Abstract
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.
Claims18
A method of treating cancer, psoriasis, restenosis, or other cell proliferative disease, 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
- R1—(C═O)— represents an acyl N-terminal blocking group;
- R2 represents H, lower alkyl, or a mono- or di-hydroxy-substituted lower alkyl;
- R3 represents lower alkyl;
- R4 is absent
- R5 represents a hydrophobic amino acid sidechain;
- R6 represents alkyl, cycloalkyl, aryl, heterocycle or —(CH2)n—R7;
- R7 represents aryl, aralkyl, cycloalkyl, alkoxy, alkylthio, —OH or —SH;
- R11 represents H or lower alkyl;
- W represents
- Y1 and Y2 are independently OH, or a group capable of being hydrolyzed to a hydroxyl group;
- or Y1 and Y2 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.
Dependencies are inferred from the claim text.