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.
Claims21
A FAP-activated prodrug of a proteasome inhibitor represented by formula I:
- A-B I
- or a pharmaceutically acceptable salt thereof, wherein
- A is Ser-(d)-Ala-Pro or (blocking group)-Ser-(d)-Ala-Pro, wherein the N-terminus of Ser is substituted with the blocking group;
- B is
- A and B being covalently linked by a bond that is enzymatically cleaved by FAP to release B in the free form;
- and
- the prodrug has a kcat/Km for FAP cleavage of the bond linking A and B of at least 10 fold more than for Prolyl endopeptidase EC 3.4.14.5 (PREP).
Dependencies are inferred from the claim text.