# US 10,117,887 B2 · FAP-activated therapeutic agents, and uses related thereto > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,117,887 B2 - Document ID: US10117887B2 - Status: Granted - Kind: B2 - Application number: 15/655,317 - Filed: 2017-07-20 - Published: 2017-11-09 - Granted: 2018-11-06 - Earliest claimed: 2014-06-13 - Assignees: Bach Biosciences, LLC - Applicants: Trustees of Tufts College - Inventors: William W. Bachovchin; Hung-sen Lai; David G. Sanford; Sarah E. Poplawski; Wengen Wu - Web page: https://patentgrep.com/patent/US10117887B2 ## CPC - A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)} - A61K 47/545: {Heterocyclic compounds (A61K47/558 takes precedence)} - A61K 47/62: the modifying agent being a protein, peptide or polyamino acid - A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) ## 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. ## Claims ### Claim 1 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 represents an N-terminally blocked alpha amino acid residue, wherein X is O; R2 represents H or a (C1-C6)alkyl; R3 represents 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 represents a self-immolative linker; and Cyt′ represents a radical of an anthracycline or derivative thereof. ### Claim 2 (depends on 1) The prodrug of claim 1, wherein L is a bond. ### Claim 3 (depends on 1) The prodrug of claim 1, wherein the anthracycline or derivative thereof is doxorubicin. ### Claim 4 (depends on 1) The prodrug of claim 1, wherein L is a self-immolative linker. ### Claim 5 (depends on 4) The prodrug of claim 4, wherein the anthracycline or derivative thereof is doxorubicin. ### Claim 6 (depends on 1) The prodrug of claim 1, wherein R2 is H. ### Claim 7 (depends on 1) The prodrug of claim 1, wherein R3 is methyl, ethyl, propyl, or isopropyl. ### Claim 8 (depends on 1) The prodrug of claim 1, wherein R3 is methyl. ### Claim 9 (depends on 1) The prodrug of claim 1, wherein represents an N-terminally blocked alpha amino acid residue, wherein X is O, which comprises a moiety which, at physiological pH, reduces cell permeability of the prodrug relative to the anthracycline or derivative thereof. ### Claim 10 (depends on 1) The prodrug of claim 1, wherein represents an N-terminally blocked alpha amino acid residue, wherein X is O, which comprises one or more functional groups that are ionized at physiological pH. ### Claim 11 (depends on 1) The prodrug of claim 1, wherein represents an N-terminally blocked alpha amino acid residue, wherein X is O, and the terminal blocking group is an acyl(C1-C10)alkyl substituted with one or more functional groups that are ionized at physiological pH. ### Claim 12 (depends on 11) The prodrug of claim 11, wherein represents an N-terminally blocked alpha amino acid residue, wherein X is O, and the terminal blocking group is represented by the formula HO2C—(C1-C10)alkyl-C(O)—. ### Claim 13 (depends on 11) The prodrug of claim 11, wherein represents an N-terminally blocked alpha amino acid residue, wherein X is O, and the terminal blocking group is represented by the formula HO2C—(CH2)2—C(O)—. ### Claim 14 (depends on 1) The prodrug of claim 1, wherein represents an N-terminally blocked alpha amino acid residue, wherein X is O, and the terminal blocking group is selected from the group consisting of formyl, dansyl, acetyl, benzoyl, trifluoroacetyl, succinyl, and methoxysuccinyl. ### Claim 15 (depends on 1) The prodrug of claim 1, wherein represents an N-terminally blocked alpha amino acid residue, wherein X is O, and the terminal blocking group is selected from the group consisting of aryl(C1-C6)acyl and heteroaryl(C1-C6)acyl. ### Claim 16 (depends on 15) The prodrug of claim 15, wherein represents an N-terminally blocked alpha amino acid residue, wherein X is O, and the terminal blocking group is an aryl(C1-C6)acyl. ### Claim 17 (depends on 16) The prodrug of claim 16, wherein the aryl(C1-C6)acyl is a (C1-C6)acyl substituted with an aryl selected from the group consisting of benzyl, naphthalenyl, phenanthrenyl, phenolyl, and anilinyl. ### Claim 18 (depends on 17) The prodrug of claim 17, wherein the aryl(C1-C6)acyl is a (C1)acyl substituted with an aryl selected from the group consisting of benzyl, naphthalenyl, phenanthrenyl, phenolyl, and anilinyl. ### Claim 19 (depends on 15) The prodrug of claim 15, wherein represents an N-terminally blocked alpha amino acid residue, wherein X is O, and R1 is a heteroaryl(C1-C6)acyl. ### Claim 20 (depends on 19) The prodrug of claim 19, wherein the heteroaryl(C1-C6)acyl is a (C1-C6)acyl substituted with a heteroaryl selected from the group consisting of pyrryl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl. ### Claim 21 (depends on 20) The prodrug of claim 20, wherein the heteroaryl(C1-C6)acyl is a (C1)acyl substituted with a heteroaryl selected from the group consisting of pyrryl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl. ### Claim 22 (depends on 1) The prodrug of claim 1, represented by the formula ### Claim 23 (depends on 1) A pharmaceutical composition, comprising a prodrug of claim 1, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. ### Claim 24 (depends on 1) A method of treating a disorder in which fibroblast activation protein (FAP) is upregulated, comprising administering to a subject in need thereof a therapeutically effective amount of a prodrug of claim 1, or a pharmaceutically acceptable salt thereof. ### Claim 25 (depends on 24) The method of claim 24, wherein the disorder is selected from the group consisting of cancer, fibrosis, and inflammation. ### Claim 26 (depends on 24) The method of claim 24, wherein the disorder is cancer. ### Claim 27 (depends on 24) The method of claim 24, wherein the disorder is fibrosis. ### Claim 28 (depends on 24) The method of claim 24, wherein the disorder is inflammation. ### Claim 29 (depends on 1) The prodrug of claim 1, wherein X is O, and is acyl(C1-C10)alkyl substituted with one or more functional groups that are ionized at physiological pH. ### Claim 30 (depends on 1) The prodrug of claim 1, wherein X is O, and is HO2C—(C1-C10)alkyl-C(O)—. ### Claim 31 (depends on 1) The prodrug of claim 1, wherein X is O, and is HO2C—(CH2)2—C(O)—. ### Claim 32 (depends on 1) The prodrug of claim 1, wherein X is O, and is selected from the group consisting of formyl, dansyl, acetyl, benzoyl, trifluoroacetyl, succinyl, and methoxysuccinyl. ### Claim 33 (depends on 1) The prodrug of claim 1, wherein X is O, and is selected from the group consisting of aryl(C1-C6)acyl and heteroaryl(C1-C6)acyl. ### Claim 34 (depends on 33) The prodrug of claim 33, wherein X is O, and is aryl(C1-C6)acyl. ### Claim 35 (depends on 34) The prodrug of claim 34, wherein aryl(C1-C6)acyl is a (C1-C6)acyl substituted with an aryl selected from the group consisting of benzyl, naphthalenyl, phenanthrenyl, phenolyl, and anilinyl. ### Claim 36 (depends on 35) The prodrug of claim 35, wherein aryl(C1-C6)acyl is a (C1)acyl substituted with an aryl selected from the group consisting of benzyl, naphthalenyl, phenanthrenyl, phenolyl, and anilinyl. ### Claim 37 (depends on 33) The prodrug of claim 33, wherein X is O, and is heteroaryl(C1-C6)acyl. ### Claim 38 (depends on 37) The prodrug of claim 37, wherein heteroaryl(C1-C6)acyl is a (C1-C6)acyl substituted with a heteroaryl selected from the group consisting of pyrryl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl. ### Claim 39 (depends on 38) The prodrug of claim 38, wherein heteroaryl(C1-C6)acyl is a (C1)acyl substituted with a heteroaryl selected from the group consisting of pyrryl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl.