Small molecule ferroptosis inducers

• US 10,947,188 B2
• Filed: 06/18/2019
• Issued: 03/16/2021
• Est. Priority Date: 12/19/2016
• Status: Active Grant

• Current Assignee: Trustees Of Columbia University In The City Of New York (Columbia University)
• Original Assignee: Trustees Of Columbia University In The City Of New York (Columbia University)
• Inventors: Stockwell, Brent R., Shimada, Kenichi, Skouta, Rachid
• Primary Examiner(s): Solola, Taofiq A
• Application Number:
  US16/445,104
• Publication Number:
  US 20190315681A1
• Time in Patent Office: 637 Days
• Field of Search: 514316
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2603/18 Fluorenes; Hydrogenated fluorenes
• CPC Class Codes: C07C 311/15 Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 311/20 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 311/21 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07D 295/26 Sulfur atoms
• CPC Class Codes: C07D 309/14 Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 407/12 linked by a chain containing hetero atoms as chain links

Abstract

The present invention provides, inter alia, a compound according to formula (I):

Also provided are compositions containing a pharmaceutically acceptable carrier and a compound according to the present invention. Further provided are methods for regulating GPX4 in a cell and methods for inducing ferroptosis in a cell.

Claims

1. A compound having the structure of formula (I):

4. A composition comprising a compound according to any one of claims 1-3, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

5. A pharmaceutically acceptable salt of a compound according to any one of claims 1-3.

6. A composition comprising a pharmaceutically acceptable salt of a compound according to any one of claims 1-3 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

2. A compound having the structure of formula (II):

3. A compound according to claim 2, which is selected from the group consisting of:

7. A method for inducing ferroptosis in a cell comprising contacting the cell with an effective amount of a compound having the structure of formula (I):

10. The method according to claim 7, wherein the compound is FIN56:

11. The method according to any one of claims 7-10, wherein the cell is a mammalian cell.

12. The method according to claim 11, wherein the cell is a human cell.

13. The method according to any one of claims 7-10, wherein the cell is from a laboratory animal.

14. The method according to any one of claims 7-10, which is carried out in vitro, or ex vivo.

8. A method for inducing ferroptosis in a cell comprising contacting the cell with an effective amount of a compound having the structure of formula (II):

9. A method for inducing ferroptosis in a cell comprising contacting the cell with an effective amount of a compound selected from the group consisting of:

15. A method for decreasing GPX4 in a cell, comprising contacting the cell with an effective amount of a compound having the structure of formula (I):

18. The method according to claim 15, wherein the compound is FIN56:

19. The method according to any one of claims 15-18, wherein the cell is a mammalian cell.

16. A method for decreasing GPX4 in a cell, comprising contacting the cell with an effective amount of a compound having the structure of formula (II):

17. A method for decreasing GPX4 in a cell, comprising contacting the cell with an effective amount of a compound selected from the group consisting of: