Synergistic effect of glucocorticoid receptor agonists in combination with proteosome inhibitors for treating leukemia and myeloma

• US 9,126,997 B1
• Filed: 09/07/2011
• Issued: 09/08/2015
• Est. Priority Date: 09/07/2010
• Status: Active Grant

• Current Assignee: Northwestern University
• Original Assignee: Northwestern University
• Inventors: Budunova, Irina, Yemelyanov, Alexander
• Primary Examiner(s): Lukton, David
• Application Number:
  US13/226,865
• Time in Patent Office: 1,462 Days
• Field of Search: 546/113, 546/18, 514/300
• US Class Current: 1/1
• CPC Class Codes: A01N 43/42 condensed with carbocyclic rings
• CPC Class Codes: C07D 271/00 Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
• CPC Class Codes: C07D 471/02 in which the condensed system contains two hetero rings

Abstract

Disclosed are methods and pharmaceutical compositions for treating diseases, disorders, and conditions associated with glucocorticoid receptor (GR) expression and activity. The disclosed methods typically include administering to a patient in need thereof a proteasome inhibitor and administering to the patient in need thereof a glucocorticoid receptor (GR) agonist, either before, concurrently with, or after the proteasome inhibitor is administered.

Claims

1. A method of treating leukemia or myeloma comprising administering to a patient in need thereof a proteasome inhibitor and administering to the patient a glucocorticoid receptor (GR) agonist, wherein the proteasome inhibitor is administered before, concurrently with, or after the GR agonist is administered.

2. The method of claim 1, wherein the patient is administered an effective amount of the proteasome inhibitor for elevating GR levels in the patient.

3. The method of claim 1, wherein the patient has previously been administered a GR agonist and is exhibiting tachyphlaxis to GR agonist therapy.

4. The method of claim 1, wherein the patient has not previously been administered a OR agonist.

5. The method of claim 1, wherein the proteasome inhibitor is selected from a group consisting of peptide boronic acid compounds, NPI-0052, 2-pyrrolidone compounds, epigallocatechin 3-gallate (EGCG) analogs, PR-171, epoxomycin analogs, peptide analogs, tetrapeptide derivatives, tyropeptide A analogs, and combinations thereof.

6. The method of claim 5, wherein the proteasome inhibitor inhibits one or more enzymatic activities of a proteasome selected from β

1 subunit activity, β

2 subunit activity, and β

5 subunit activity.

7. The method of claim 5, wherein the proteasome inhibitor is a peptide boronic acid compound that reversibly inhibits subunit β

1 activity of the proteasome.

8. The method of claim 5, wherein the compound is bortezomib or a pharmaceutically acceptable salt thereof.

9. The method of claim 8, wherein the bortezomib is administered to the patient at a dosage of about 0.7 mg/m² to about 1.9 mg/m.

10. The method of claim 1, wherein the GR agonist is a selective GR agonist (SEGRA).

11. The method of claim 10, wherein the SEGRA is selected from a group consisting of (R-1,1,1-trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-{[(2-methyl-5-quinolyl)amino]methyl}pentan-2-ol) (BOL-303242-X), (2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(1-methylcyclohexen-3-yl)-1H-[1]benzopyrano[3,4-f]quinoline (A 276575U), and RU 24858 having a formula:

12. The method of claim 10, wherein the SEGRA is selected from the group of compounds consisting of

13. A method of treating myeloma comprising administering to a patient in need thereof a proteasome inhibitor and a selective GR agonist (SEGRA) to the patient.

14. The method of claim 13, wherein the proteasome inhibitor is bortezomib and the SEGRA is 2-(4-acetoxyphenyl)-2-chloro-N-methylethylammonium chloride.

15. The method of claim 13, wherein the proteasome inhibitor is administered before the GR agonist is administered.

16. The method of claim 13, wherein the proteasome inhibitor is administered concurrently with the GR agonist.

17. The method of claim 13, wherein the proteasome inhibitor is administered after the GR agonist is administered.

18. The method of claim 13, wherein the patient is administered an effective amount of the proteasome inhibitor for elevating GR levels in the patient.

19. The method of claim 13, wherein the patient has previously been administered a GR agonist and is exhibiting tachyphylaxis to GR agonist therapy.

20. The method of claim 13, wherein the patient has not previously been administered a GR agonist.