FAP-activated proteasome inhibitors for treating solid tumors

Patent metadata

Field	Value
Publication number	US-9597410-B2
Application number	US-201214241666-A
Country	US
Kind code	B2
Filing date	Aug 30, 2012
Priority date	Aug 30, 2011
Publication date	Mar 21, 2017
Grant date	Mar 21, 2017

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.

First claim

We claim:

1. A fibroblast activation protein (FAP)-activated proteasome inhibitor represented by formula II:

wherein
R 1 —(C═O)— represents an acyl N-terminal blocking group;
R 2 represents H, lower alkyl, or a mono- or di-hydroxy-substituted lower alkyl;
R 3 represents H, halogen, or lower alkyl;
R 4 is absent or represents lower alkyl, —OH, —NH 2 or halogen; and

is selected from the group consisting of:

2. A FAP-activated proteasome inhibitor represented by formula III:

wherein
R 1 —(C═O)— represents an acyl N-terminal blocking group;
R 2 represents H, lower alkyl, or a mono- or di-hydroxy-substituted lower alkyl;
R 3 represents H, halogen, or lower alkyl;
R 4 is absent or represents lower alkyl, —OH, —NH 2 or halogen;
R 5 represents a large hydrophobic amino acid sidechain;
R 6 represents alkyl, cycloalkyl, aryl, heterocycle or —(CH 2 ) n —R 7 ;
R 7 represents aryl, aralkyl, cycloalkyl, alkoxy, alkylthio, —OH or —SH;
R 11 represents H or lower alkyl;
W represents —CN, an epoxyketone, —CH═NR 8 ,

R 8 represents H, alkyl, alkenyl, alkynyl, —C(X 1 )(X 2 )X 3 , —(CH 2 ) m —R 9 , —(CH 2 ) n —OH, —(CH 2 ) n —O-alkenyl, —(CH 2 ) n —O-alkynyl, —(CH 2 ) n —O-alkynyl, —(CH 2 ) n —O—(CH 2 ) m —R 9 , —(CH 2 ) n —SH, —(CH 2 ) n —S-alkyl, —(CH 2 ) n —S-alkenyl, —(CH 2 ) n —S-alkynyl, —(CH 2 ) n —S—(CH 2 ) m —R 9 , —C(═O)C(═O)NH 2 , —C(═O)C(═O)OR 10 ;
R 9 represents, independently for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle;
R 10 represents, independently for each occurrence, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle;
Y 1 and Y 2 can independently or together be OH, or a group capable of being hydrolyzed to a hydroxyl group, including cyclic derivatives where Y 1 and Y 2 are connected via a ring having from 5 to 8 atoms in the ring structure;
R 50 represents O or S;
R 51 represents N 3 , SH 2 , NH 2 , NO 2 or —OR 10 ;
R 52 represents hydrogen, lower alkyl, amine, —OR 10 , or a pharmaceutically acceptable salt, or R 51 and R 52 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure;
X 1 is halogen;
X 2 and X 3 each represent H or halogen;
m is zero or an integer in the range of 1 to 8; and
n is an integer in the range of 1 to 8.

3. The FAP-activated proteasome inhibitor of claim 2 , represented by

4. A pharmaceutical composition, comprising a FAP-activated proteasome inhibitor of claim 1 ; and a pharmaceutically acceptable excipient.

5. A method of inhibiting proteasome function in a cell, comprising contacting the cell with an effective amount of a FAP-activated proteasome inhibitor of claim 1 .

6. A method of inhibiting antigen presentation in a cell, comprising contacting the cell with an effective amount of a FAP-activated proteasome inhibitor of claim 1 .

7. 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 FAP-activated proteasome inhibitor of claim 1 .

8. The method of claim 7 , further comprising co-administering to the mammal in need thereof a therapeutically effective amount of a chemotherapeutic agent.

9. The method of claim 8 , wherein the chemotherapeutic agent is docetaxel, paclitaxel, imatinib mesylate, gemcitabine, cis-platin, carboplatin, 5-fluorouracil, pemetrexed, methotrexate, doxorubicin, lenalidomide, dexamethasone, or monomethyl auristatin.

10. The method of claim 8 , wherein the chemotherapeutic agent is docetaxel, gemcitabine, carboplatin, or doxorubicin.

11. The method of claim 8 , wherein the chemotherapeutic agent is MG-132, PSI, fellutamide B, bortezomib, CEP-18770, MLN-2238, MLN-9708, epoxomicin, carfilzomib (PR-171), NC-005, YU-101, LU-005, YU-102, NC-001, LU-001, NC-022, PR-957 (LMP7), CPSI (β5), LMP2-sp-ek, BODIPY-NC-001, azido-NC-002, ONX-0912, omuralide, PS-519, marizomib, belactosin A, 125 I-NIP-L 3 VS, NC-005-VS, or MV151.

12. A method of inhibiting HIV infection in a mammal, comprising administering to a mammal in need thereof a therapeutically effective amount of a FAP-activated proteasome inhibitor of claim 1 .

13. The FAP-activated proteasome inhibitor of claim 2 , wherein the acyl N-terminal blocking group is selected from the group consisting of formyl, acetyl, benzoyl, trifluoroacetyl, succinyl and methoxysuccinyl.

14. The FAP-activated proteasome inhibitor of claim 2 , wherein the acyl N-terminal blocking group is represented by the formula —C(═O)—(CH 2 ) 1-10 —C(═O)—OH.

15. The FAP-activated proteasome inhibitor of claim 2 , wherein the acyl N-terminal blocking group is succinyl.

16. The FAP-activated proteasome inhibitor of claim 2 , wherein the acyl N-terminal blocking group is selected from the group consisting of aryl(C 1 -C 6 )acyl, and heteroaryl(C 1 -C 6 )acyl.

17. The FAP-activated proteasome inhibitor of claim 16 , wherein the acyl N-terminal blocking group is an aryl(C 1 -C 6 )acyl, wherein aryl(C 1 -C 6 )acyl is a (C 1 -C 6 )acyl substituted with an aryl selected from the group consisting of benzene, naphthalene, phenanthrene, phenol and aniline.

18. The FAP-activated proteasome inhibitor of claim 16 , wherein the acyl N-terminal blocking group is an heteroaryl(C 1 -C 6 )acyl, wherein heteroaryl(C 1 -C 6 )acyl is a (C 1 -C 6 )acyl substituted with a heteroaryl selected from the group consisting of pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine.

19. A pharmaceutical composition, comprising a FAP-activated proteasome inhibitor of claim 2 ; and a pharmaceutically acceptable excipient.

20. A method of inhibiting proteasome function in a cell, comprising contacting the cell with an effective amount of a FAP-activated proteasome inhibitor of claim 2 .

21. A method of inhibiting antigen presentation in a cell, comprising contacting the cell with an effective amount of a FAP-activated proteasome inhibitor of claim 2 .

22. 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 FAP-activated proteasome inhibitor of claim 2 .

23. The method of claim 22 , further comprising co-administering to the mammal in need thereof a therapeutically effective amount of a chemotherapeutic agent.

24. The method of claim 23 , wherein the

Assignees

• Bachovchin William W
• Lai Hung-Sen
• Poplawski Sarah E
• Tufts College

Inventors

• Bachovchin William W
• Lai Hung-Sen
• Poplawski Sarah E

Classifications

• G01N33/575

  for cancer · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P17/06

  Antipsoriatics · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61K47/54

  the modifying agent being an organic compound · CPC title