Small molecule inhibitors of XBP1 splicing

Patent metadata

Field	Value
Publication number	US-10806725-B2
Application number	US-201615155258-A
Country	US
Kind code	B2
Filing date	May 16, 2016
Priority date	Apr 4, 2011
Publication date	Oct 20, 2020
Grant date	Oct 20, 2020

Abstract

Small molecule inhibitors of XBP1 splicing by IRE1α are provided, as well as methods for their use in treating or preventing cancer (e.g., endocrine resistant breast cancer), diabetes, and obesity.

First claim

What is claimed is:

1. A method of treating breast cancer in a subject comprising administering to the subject one or more compounds of the following structure:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:
L is —C(═O)NH—, —NHC(═O)—, —C(═O)O—, —C(═O)—CH 2 —,

R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen, halogen, hydroxyl, trifluoromethyl, alkyl, heteroalkyl, amino, or alkoxyl;
R 5 is substituted or unsubstituted aryl, cycloalkyl, alkynyl, or dansyl, wherein substituted aryl is substituted with alkyl, alkoxy, halogen, or haloalkyl; and
X is aryl, heteroaryl, or cycloalkyl.

2. The method of claim 1 , wherein R 1 , R 2 , R 3 , and R 4 are each hydrogen, R 5 is substituted or unsubstituted phenyl, L is —C(═O)NH—, and X is phenyl or pyridyl.

3. The method of claim 1 , wherein R 1 , R 2 , R 3 , and R 4 are each hydrogen, R 5 is unsubstituted phenyl, L is —C(═O)NH—, and X is phenyl.

4. The method of claim 1 , wherein R 1 , R 2 , R 3 , and R 4 are each hydrogen, R 5 is substituted phenyl, L is —C(═O)NH—, and X is pyridyl.

5. The method of claim 1 , wherein R 1 , R 2 , R 3 , and R 4 are each hydrogen.

6. The method of claim 1 , wherein R 5 is substituted or unsubstituted phenyl.

7. The method of claim 1 , wherein L is —C(═O)NH—.

8. The method of claim 1 , wherein X is aryl.

9. The method of claim 1 , wherein X is phenyl.

10. The method of claim 1 , wherein X is heteroaryl.

11. The method of claim 1 , wherein X is pyridyl.

12. The method of claim 1 , wherein the breast cancer is endocrine resistant breast cancer.

13. The method of claim 1 , wherein the breast cancer is anti-estrogen resistant breast cancer.

14. A method of treating breast cancer in a subject comprising administering to the subject one or more compounds of the following structure:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:
L is —C(═O)NH—;
R 1 , R 2 , R 3 , and R 4 are each hydrogen;
R 5 is substituted or unsubstituted phenyl; and
X is phenyl or pyridyl.

15. The method of claim 14 , wherein R 5 is unsubstituted phenyl, and X is unsubstituted phenyl.

16. The method of claim 14 , wherein R 5 is substituted phenyl, and X is pyridyl.

Assignees

• Univ Georgetown

Inventors

• Dakshanamurthy Sivanesan
• Brown Milton L
• Clarke Robert
• Shajahan-Haq Ayesha N
• Smith Jacqueline

Classifications

• C07D405/14

  containing three or more hetero rings · CPC title

• A61K31/4439 Primary

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

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title

• C07D213/32

  Sulfur atoms · CPC title

• A61P35/00

  Antineoplastic agents · CPC title