Compounds and methods useful for treating or preventing hematological cancers

Patent metadata

Field	Value
Publication number	US-11096934-B2
Application number	US-201615756469-A
Country	US
Kind code	B2
Filing date	Aug 29, 2016
Priority date	Sep 1, 2015
Publication date	Aug 24, 2021
Grant date	Aug 24, 2021

Abstract

The present invention includes methods of treating patients with acute myeloid leukemia across a range of genetic subtypes with DHODH inhibitors, such as 6-fluoro-2-(2′-fluoro-[1,1′-biphenyl]-4-yl)-3-methylquinoline-4-carboxylic acid).

First claim

The invention claimed is:

1. A method of treating a hematological cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a dihydroorotate dehydrogenase (DHODH) inhibitor, wherein the dihydroorotate inhibitor is selected from the group consisting of 6-fluoro-2-(2′-fluoro-[1,1′-biphenyl]-4-yl)-3-methylquinoline-4-carboxylic acid; salts, or solvates thereof; wherein said DHODH inhibitor is administered to the subject with a frequency less than or equal to once every 48 hours; wherein said administration results in intermittent periods of nucleotide depletion that differentially starves malignant cells as compared to normal cells; and wherein the 6-fluoro-2-(2′-fluoro-[1,1′-biphenyl]-4-yl)-3-methylquinoline-4-carboxylic acid is administered to the subject by injection.

2. The method according to claim 1 , wherein 6-fluoro-2-(2′-fluoro-[1,1′-biphenyl]-4-yl)-3-methylquinoline-4-carboxylic acid or a salt or solvate thereof is administered to the subject with a frequency less than or equal to once every 72 hours.

3. The method according to claim 1 , wherein the hematological cancer comprises acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), mixed-lineage leukemia (MLL), myelodysplastic syndrome (MDS), and/or chronic myeloid leukemia (CML).

4. The method according to claim 3 , wherein the hematological cancer comprises AML.

5. The method according to claim 1 , wherein the subject has been treated or is being treated for a hematological cancer characterized by differentiation arrest.

6. The method according to claim 1 , wherein 6-fluoro-2-(2′-fluoro-[1,1′-biphenyl]-4-yl)-3-methylquinoline-4-carboxylic acid is administered to the subject by an injection route selected from intravenous, intradermal, intramuscular, subcutaneous, intracutaneous, intrauterine, epidural and intracerebroventricular injections.

7. The method according to claim 1 , wherein at least one additional agent useful for treating a hematological cancer is further administered to the subject.

8. The method according to claim 7 , wherein the additional agent is arsenic trioxide.

9. The method according claim 1 , wherein the subject is not responsive to one or more anticancer agents.

10. The method according to claim 1 , wherein the method comprises administering to the subject a composition comprising a dihydroorotate dehydrogenase (DHODH) inhibitor in an amount and for a duration sufficient to increase levels of dihydroorotate and/or to reduce levels of uridine in a biological sample obtained from the subject, thereby treating the hematological cancer.

Assignees

• Broad Inst Inc
• Massachusetts Gen Hospital
• Harvard College
• Bayer Pharma AG

Inventors

• Sykes David B
• Scadden David
• Lewis Timothy A
• Janzer Andreas
• Meyer Hanna
• Stöckigt Detlef

Classifications

• A61K33/36

  Arsenic; Compounds thereof · CPC title

• A61K31/42

  Oxazoles · CPC title

• A61K31/277

  having a ring, e.g. verapamil · CPC title

• A61K31/27

  of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine · CPC title

• A61K31/47 Primary

  Quinolines; Isoquinolines · CPC title