FAP-Activated Proteasome Inhibitors for Treating Solid Tumors

Patent metadata

Field	Value
Publication number	US-2016346401-A1
Application number	US-201615167109-A
Country	US
Kind code	A1
Filing date	May 27, 2016
Priority date	Aug 30, 2011
Publication date	Dec 1, 2016
Grant date	—

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

1 - 53 . (canceled)

61 . 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 fibroblast activation protein (FAP)-activated proteasome inhibitor represented by formula I:

or a pharmaceutically acceptable salt thereof,
wherein
X—C(═O)NR 11 —R′ 5 — represents a FAP substrate sequence;
X is an N-acyl peptidyl group;
—NR 11 —R′ 5 is an amino acid residue or analog thereof that binds the P′ 1 specificity subsite of FAP;
the FAP substrate sequence is cleaved by FAP to release NHR 11 —R′ 5 —R;
R 11 represents H or lower alkyl; and
NHR 11 —R′ 5 —R is a proteasome inhibitor.

62 . The method of claim 61 , further comprising co-administering to the mammal and a therapeutically effective amount of a chemotherapeutic agent.

63 . The method of claim 62 , wherein the chemotherapeutic agent is docetaxel, paclitaxel, imatinib mesylate, gemcitabine, cis-platin, carboplatin, 5-fluorouracil, pemetrexed, methotrexate, doxorubicin, lenalidomide, dexamethasone, or monomethyl auristatin.

64 . The method of claim 62 , wherein the chemotherapeutic agent is docetaxel, gemcitabine, carboplatin, or doxorubicin.

65 . The method of claim 62 , 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 (J35), 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.

66 - 122 . (canceled)

123 . The method of claim 61 , wherein the FAP-activated proteasome inhibitor is 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;
R 5 represents a large hydrophobic amino acid sidechain;
R 11 represents H or lower alkyl; and
the FAP-activated proteasome inhibitor is cleaved by FAP to release a proteasome inhibitor represented by

124 . The method of claim 123 , wherein proteasome inhibitor is selected from the group consisting of:

125 . The method of claim 123 , wherein the FAP-activated proteasome inhibitor of claim, 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 5 ,

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-alkyl, —(CH 2 ) n —O-alkenyl, —(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.

125 . The method of claim 124 , wherein the FAP-activated proteasome inhibitor is represented by

126 . The method of claim 61 , wherein the method is a method of treating cancer.

127 . The method of claim 126 , wherein the cancer is a solid tumor.

128 . The method of claim 127 , wherein the solid tumor is selected from prostate, pancreatic, or breast cancer.

129 . The method of claim 126 , wherein the cancer is pancreatic cancer.

130 . The method of claim 126 , wherein the cancer in multiple myeloma.

131 . 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 fibroblast activation protein (FAP)-activated prodrug of a proteasome inhibitor represented by A-B, or a pharmaceutically acceptable salt thereof, wherein
A represents a substrate for FAP; B represents a proteasome inhibitor moiety which, when released in a free form from the prodrug as a product of cleavage by FAP, inhibits the proteolytic activity of a proteasome with a Ki of 500 nM or less; A and B being covalently linked by a bond that is enzymatically cleaved by FAP to release B in said free form; and the prodrug has a k cat /K m for FAP cleavage of the bond linking A and B of at least 10 fold more than for prolyl endopeptidase EC 3.4.21.26 (PREP).

132 . 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 compound or a pharmaceutically acceptable salt thereof represented by the formula:
R—Xaa 1 —Xaa 2 -Y

wherein
R is an acyl group;
Xaa 1 is selected from the group consisting of Ala, Cys, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, and Tyr;
Xaa 2 is selected from the group consisting of Ala, Cys, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, and Tyr; and
Y is

Assignees

• Tufts College

Inventors

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

Classifications

• G01N33/575

  for cancer · 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

• A61P35/00

  Antineoplastic agents · CPC title

• C07K5/0806

  the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala · CPC title