Use of bromodomain-containing protein 9 antagonists in combination with vitamin D receptor agonists in diabetes treatment

Patent metadata

Field	Value
Publication number	US-11376264-B2
Application number	US-202016737312-A
Country	US
Kind code	B2
Filing date	Jan 8, 2020
Priority date	Jul 24, 2017
Publication date	Jul 5, 2022
Grant date	Jul 5, 2022

Abstract

Methods are provided for reducing blood glucose, which utilize an agent that increases the biological activity of a vitamin D receptor (VDR) (e.g., a VDR agonist), in combination with an antagonist of bromodomain-containing protein 9 (BRD9). IN some examples, such methods treat type II diabetes.

First claim

We claim:

1. A method of reducing blood glucose in a mammal, comprising:
administering a therapeutically effective amount of one or more vitamin D receptor (VDR) agonists to the mammal, wherein the one or more VDR agonists is calcipotriol, 25-hydroxy-D 3 (25-OH-D 3 ) (calcidiol); vitamin D3 (cholecalciferol); vitamin D2 (ergocalciferol), 1α,25-dihydroxyvitamin D 3 (calcitriol), or a combination thereof, and
administering a therapeutically effective amount of one or more bromodomain-containing protein 9 (BRD9) antagonists to the mammal, wherein the one or more BRD9) antagonists is I-BRD-9, TP742, BI-7273, BI-9564, dBRD9, GNE-375, LP-99, or a combination thereof,
thereby reducing blood glucose in the mammal.

2. A method of treating type 2 diabetes in a mammal, comprising:
administering a therapeutically effective amount of one or more vitamin D receptor (VDR) agonists to the mammal, wherein the one or more VDR agonists is calcipotriol, 25-hydroxy-D 3 (25-OH-D 3 ) (calcidiol); vitamin D3 (cholecalciferol): vitamin D2 (ergocalciferol), 1α,25-dihydroxyvitamin D 3 (calcitriol), or a combination thereof, and
administering a therapeutically effective amount of one or more bromodomain-containing protein 9 (BRD9) antagonists to the mammal, wherein the one or more BRD9) antagonists is I-BRD-9, TP742, BI-7273, BI-9564, dBRD9, GNE-375, LP-99, or a combination thereof,
thereby treating type 2 diabetes in the mammal.

3. A method, comprising:
administering a therapeutically effective amount of one or more vitamin D receptor (VDR) agonists to a mammal, wherein the one or more VDR agonists is calcipotriol, 25-hydroxy-D 3 (25-OH-D 3 ) (calcidiol); vitamin D3 (cholecalciferol); vitamin D2 (ergocalciferol), 1α,25-dihydroxyvitamin D 3 (calcitriol), or a combination thereof, and
administering a therapeutically effective amount of one or more bromodomain-containing protein 9 (BRD9) antagonists to the mammal, wherein the one or more BRD9) antagonists is I-BRD-9, TP742, BI-7273, BI-9564, dBRD9, GNE-375, LP-99, or a combination thereof,
wherein the method reduces fed and fasting blood glucose, increases insulin sensitivity, increases glucose tolerance, increases insulin secretion, increases beta cell function, increases the size of islets, reduced beta cell death, increases insulin granules, or combinations thereof, in the mammal.

4. The method of claim 1 , wherein the therapeutically effective amount of the one or more VDR agonists is at least 0.01 mg/kg, the therapeutically effective amount of the one or more BRD9 antagonists is at least 0.1 mg/kg, or both.

5. The method of claim 1 , wherein the administering is subcutaneous, intraperitoneal, intramuscular, intravenous or intrathecal.

6. The method of claim 1 , wherein the mammal is a cat or dog.

7. The method of claim 1 , wherein the mammal is a human.

8. The method of claim 2 , wherein the VDR agonist is calcipotriol and the BRD9 antagonist is I-BRD9.

9. The method of claim 3 , wherein the VDR agonist is calcipotriol and the BRD9 antagonist is I-BRD-9.

10. The method of claim 2 , wherein the method further comprises administering an additional therapeutic compound.

11. The method of claim 1 , wherein the VDR agonist is calcipotriol and the BRD9 antagonists is I-BRD9.

12. The method of claim 1 , wherein the one or more VDR agonists and one or more BRD9 antagonists are administered concurrently.

13. The method of claim 1 , wherein the one or more VDR agonists and one or more BRD9 antagonists are administered sequentially.

14. The method of claim 1 , wherein the one or more VDR agonists, one or more BRD9 antagonists, or both, are part of a nanoparticle.

15. The method of claim 1 , wherein the method further comprises administering an additional therapeutic compound.

16. The method of claim 15 , wherein the additional therapeutic compound is insulin, an alpha-glucosidase inhibitor, amylin agonist, dipeptidyl-peptidase 4 (DPP-4) inhibitor, meglitinide, sulfonylurea, or a peroxisome proliferator-activated receptor (PPAR)-gamma agonist.

17. The method of claim 16 , wherein the PPAR-gamma agonist is a thiazolidinedione (TZD), aleglitazar, farglitazar, muraglitazar, or tesaglitazar.

18. The method of claim 17 , wherein the TZD is pioglitazone, rosiglitazone, rivoglitazone, or troglitazone.

Assignees

• Salk Inst For Biological Studi

Inventors

• Evans Ronald M
• Downes Michael
• Wei Zong
• Atkins Annette
• Yu Ruth T

Classifications

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K31/593

  9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3 · CPC title

• A61K31/59 Primary

  Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems · CPC title

• A61K31/4365

  the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title