Fap-activated therapeutic agents, and uses related thereto

A method of treating a disorder characterized by fibroblast activation protein (FAP) upregulation, comprising administering to a subject in need thereof a therapeutically effective amount of a prodrug represented by the general formula:

• 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 and X is O;
• R2 represents H or a (C1-C6)alkyl;
• R3 represents (C1-C6)alkyl;
• R4 is absent or represents one, two or three substituents, each independently selected from the group consisting of a (C1-C6)alkyl, —OH, —NH2, or halogen;
• X represents O or S;
• Cyt′ represents a taxane;
• and
• L represents a bond or a self-immolative linker which is metabolized after FAP cleavage of the prodrug to release the taxane
• wherein the prodrug is selectively converted to the taxane by FAP+ stromal cells.

A method of treating a disorder characterized by fibroblast activation protein (FAP) upregulation, comprising administering to a subject in need thereof a therapeutically effective amount of a prodrug represented by the general formula:

• or a pharmaceutically acceptable salt thereof, wherein:
• Cyt′ represents a taxane;
• R1, taken together as —C(═X)R1, represents a moiety which at physiological pH reduces cell permeability of the prodrug relative to the taxane;
• R2 represents H or a (C1-C6)alkyl;
• R3 represents (C6-C6)alkyl;
• R4 is absent or represents one, two or three substituents, each independently selected from the group consisting of a (C1-C6)alkyl, —OH, —NH2, or halogen;
• X represents O or S;
• and
• L represents a bond or a self-immolative linker which is metabolized after FAP cleavage of the prodrug to release the taxane;
• wherein the prodrug is selectively converted to the taxane by FAP+ stromal cells.