FAP-Activated Therapeutic Agents, and Uses Related Thereto
AssigneeTrustees of Tufts College
InventorsWilliam W. Bachovchin, Hung-sen Lai, David G. Sanford, Sarah E. Poplawski, Wengen Wu
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Abstract
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.
Claims32
A prodrug represented by Formula I:
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 represents (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkyl-C(O)—(C1-C10)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C10)alkyl, aryl, aryl(C1-C10)alkyl, heteroaryl, or heteroaryl(C1-C10)alkyl, wherein any R1 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 —C(X)R1 represents an N-terminally blocked alpha amino acid residue, wherein X is O;
- R2 represents H or a (C1-C6)alkyl;
- R3 represents H or a (C1-C6)alkyl;
- R4 is absent or represents a (C1-C6)alkyl, —OH, —NH2, or 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.
32-36. (canceled)
Dependencies are inferred from the claim text.