Glutaminase inhibitor therapy

Patent metadata

Field	Value
Publication number	US-11045443-B2
Application number	US-202016891791-A
Country	US
Kind code	B2
Filing date	Jun 3, 2020
Priority date	Oct 18, 2017
Publication date	Jun 29, 2021
Grant date	Jun 29, 2021

Abstract

Disclosed herein are methods of treating a tumor or cancer in a subject whose tumor or cancer cells express low levels of asparagine synthetase (ASNS), and compounds and compositions useful in such treatment. Also disclosed herein are methods of evaluating whether to administer a compound that inhibits glutathione production or a glutaminase inhibitor to a subject with a tumor or cancer.

First claim

What is claimed is:

1. A method of treating cancer in a subject whose cancer cells express low levels of asparagine synthetase (ASNS), as defined by an Histophathology Score (H-score) of less than or equal to 100 by immunohistochemical staining, comprising administering a glutaminase (GLS) inhibitor to said subject.

2. The method of claim 1 wherein the GLS inhibitor is selective for glutaminase-1 (GLS-1).

3. The method of claim 2 , wherein the cancer is chosen from bladder cancer, bone marrow cancer, breast cancer, cancer of the central nervous system, cervical cancer, colon cancer, endometrial cancer, cancer of the gastric system, head and neck cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, muscle cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, thyroid cancer, or a variant thereof.

4. The method of claim 3 , wherein the cancer is chosen from ovarian, skin, liver, prostate, breast, colon, lung, head and neck cancers or a lymphoma.

5. The method of claim 4 , wherein the cancer is ovarian cancer.

6. The method of claim 5 , wherein the ovarian cancer is high-grade serous ovarian cancer (HGSOC).

7. The method of claim 6 , wherein the ovarian cancer is nonresectable or relapsed HGSOC.

8. The method of claim 5 , further comprising administering another pharmaceutically active compound.

9. The method of claim 8 , wherein said another pharmaceutically active compound is chosen from carboplatin, cisplatin, paclitaxel, and docetaxel.

10. The method of claim 9 , wherein said another pharmaceutically active compound is chosen from carboplatin and cisplatin.

11. The method of claim 9 , wherein said another pharmaceutically active compound is chosen from paclitaxel and docetaxel.

12. The method of claim 11 , wherein said another pharmaceutically active compound is paclitaxel.

13. The method of claim 2 , wherein the GLS-1 inhibitor binds an allosteric pocket on the solvent-exposed region of the GLS-1 dimer in the binding pocket present in the vicinity of Leu321, Phe322, Leu323, and Tyr394 from both monomers.

14. The method of claim 2 , wherein the GLS-1 inhibitor has Formula I:

or a salt thereof, wherein:
n is chosen from 3, 4, and 5;
each R x and R y is independently chosen from alkyl, cyano, H, and halo, wherein two R x groups together with the atoms to which they are attached optionally form a cycloalkyl ring;
A 1 and A 2 are independently chosen from C—H, C—F, and N;
R 1 and R 4 are independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxyl, C(R 3 ) 2 C(O)R 3 , C(R 3 ) 2 C(O)N(R 3 ) 2 , C(R 3 ) 2 N(R 3 ) 2 , C(R 3 ) 2 NR 3 C(O)R 3 , C(R 3 ) 2 NR 3 C(O)OR 3 , C(R 3 ) 2 NR 3 C(O)N(R 3 ) 2 , C(R 3 ) 2 NR 3 S(O)R 3 , C(R 3 ) 2 NR 3 S(O) 2 R 3 , N(R 3 ) 2 , NR 3 C(O)R 3 , NR 3 C(O)OR 3 , NR 3 C(O)N(R 3 ) 2 , NR 3 S(O)R 3 , NR 3 S(O) 2 R 3 , C(O)N(R 3 ) 2 , S(O)N(R 3 ) 2 , S(O) 2 N(R 3 ) 2 , C(O)R 3 , SR 3 , S(O)R 3 , and S(O) 2 R 3 , wherein each R 1 and R 4 may be optionally substituted with between 0 and 3 R z groups;
R 2 is chosen from alkyl, heterocycloalkyl, cyano, cycloalkyl, H, halo, and haloalkyl, wherein R 1 and R 2 together with the atoms to which they are attached optionally form an form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R z groups;
each R 3 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein each R 3 may be optionally substituted with between 0 and 3 R z groups, wherein two R 3 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R z groups;
each R Z group is independently chosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylhaloalkyl, cycloalkyloxy, H, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl, haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl, haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy, haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy, haloheterocycloalkyloxy, heteroaryl, heteroarylalkyl, heteroarylalkyloxy, heteroarylhaloalkyl, heteroaryloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy, heterocycloalkylhaloalkyl, heterocycloalkyloxy, hydroxyl, oxo, N(R 6 ) 2 , NR 6 C(O)C(R 6 ) 3 , NR 6 C(O)OC(R 6 ) 3 , NR 6 C(O)N(R 6 ) 2 , NR 6 S(O)C(R 6 ) 3 , NR 6 S(O) 2 C(R 6 ) 3 , C(O)N(R 6 ) 2 , S(O)N(R 6 ) 2 , S(O) 2 N(R 6 ) 2 , C(O)C(R 6 ) 3 , SC(R 6 ) 3 , S(O)C(R 6 ) 3 , and S(O) 2 C(R 6 ) 3 ;
each R 6 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein two R 6 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R x groups; and
Z is heteroaryl, which may be optionally substituted.

15. The method of claim 2 , wherein the GLS-1 inhibitor has Formula II:

or a salt thereof, wherein:
n is chosen from 3, 4, and 5;
each R x and R y is independently chosen from alkyl, cyano, H, and halo, wherein two R x groups together with the atoms to which they are attached optionally form a cycloalkyl ring;
A 1 and A 2 are independently chosen from N and CH;
A 3 is chosen from N and CR 2 ;
R 1 is chosen from alkenyl, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, C(O)N(R 3 ) 2 , and C(O)C(R 3 ) 3 , wherein R 1 may be optionally substituted with between 0 and 3 R z groups,
R 2 is chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxyl, C(O)N(R 3 ) 2 , C(O)C(R 3 ) 3 , C(O)OH, C(O)OC(R 3 ) 3 , wherein R 1 and R 2 together with the atoms to which they are attached optionally form an form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R z grou

Assignees

• Univ Texas

Inventors

• Heffernan Timothy
• Kovacs Jeffrey
• Spencer Nakia
• Bristow Christopher

Classifications

• G01N33/57545

  of the ovaries · CPC title

• A61K31/282 Primary

  Platinum compounds · CPC title

• A61K31/433

  Thidiazoles · CPC title

• A61K31/337

  having four-membered rings, e.g. taxol · CPC title

• A61K31/501

  not condensed and containing further heterocyclic rings · CPC title