Therapeutic targeting of the interleukin 1 receptor-associated kinase 4 (IRAK4) in leukemias characterized by rearrangements in the mixed lineage leukemia gene (MLL-r)

• US 10,059,708 B2
• Filed: 04/26/2017
• Issued: 08/28/2018
• Est. Priority Date: 04/26/2016
• Status: Active Grant

• Current Assignee: Northwestern University
• Original Assignee: Northwestern University
• Inventors: Shilatifard, Ali, Liang, Kaiwei, Smith, Edwin Richard
• Primary Examiner(s): Ivanova, Svetlana M
• Application Number:
  US15/497,783
• Publication Number:
  US 20170305901A1
• Time in Patent Office: 489 Days
• Field of Search: None
• CPC Class Codes: C07D 233/88 Nitrogen atoms, e.g. allantoin
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Disclosed are methods for treating cancers associated with rearrangements in the mixed lineage leukemia gene (MLL-r), including MLL-r leukemia. The methods typically include administering a therapeutic amount of one or more therapeutic agents that inhibit the biological activity of one or more members of the interleukin-1 signaling pathway such inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4).

Claims

1. A method for treating a cancer characterized by a rearrangement in the mixed lineage leukemia gene (MLL-r) in a subject in need thereof, wherein the cancer is MLL-r leukemia, the method comprising administering a therapeutic amount of a therapeutic agent that inhibits the biological activity of interleukin-1 receptor-associated kinase 4 (IRAK4), wherein the therapeutic agent comprises a compound having a formula:

2. A compound having a formula:

3. The compound of claim 2, wherein at least one of R², R³, R⁴, R⁷, R⁸, and R⁹ is not hydrogen.

4. The compound of claim 2, wherein at least one of R², R³, and R⁴ is halo or alkyoxy and at least one of R⁷, R⁸, and R⁹ is amino, alkyl-substituted amino, dialkyl-substituted amino, amido, cyano, nitro, hydroxyl, or halo.

5. The compound of claim 2, wherein the compound has a formula selected from:

6. The compound of claim 2, wherein the compound has a formula selected from:

7. A pharmaceutical composition comprising the compound of claim 2 and a pharmaceutically acceptable carrier.

8. A pharmaceutical composition comprising the compound of claim 3 and a pharmaceutically acceptable carrier.

9. A pharmaceutical composition comprising the compound of claim 4 and a pharmaceutically acceptable carrier.

10. A pharmaceutical composition comprising the compound of claim 5 and a pharmaceutically acceptable carrier.

11. A pharmaceutical composition comprising the compound of claim 6 and a pharmaceutically acceptable carrier.

12. A method for treating MLL-r leukemia in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 7.

13. A method for treating MLL-r leukemia in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 8.

14. A method for treating MLL-r leukemia in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 9.

15. A method for treating MLL-r leukemia in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 10.

16. A method for treating MLL-r leukemia in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 11.