CYCLIC PEPTIDE INHIBITORS OF LYSINE-SPECIFIC DEMETHYLASE 1

• US 20150065434A1
• Filed: 08/29/2014
• Published: 03/05/2015
• Est. Priority Date: 08/29/2013
• Status: Active Grant

• Current Assignee: MUSC Foundation For Research Development (State of South Carolina)
• Original Assignee: MUSC Foundation For Research Development (State of South Carolina)
• Inventors: WOSTER, Patrick M., KUMARASINGHE, Isuru R.
• Granted Patent: US 9,186,391 B2
• Time in Patent Office: Days
• US Class Current: 514/19.9
• CPC Class Codes: A61K 38/1709 from mammals

Abstract

Provided herein are cyclic peptide inhibitors of lysine-specific demethylase 1. These cyclic peptides have the potential to treat cancer, diabetes, cardiovascular disease, and neurological disorders.

Claims

1. A cyclic peptide lysine-specific demethylase 1 (LSD1) inhibitor comprising a sequence at least 90% identical to the peptide sequence of SEQ ID NO:

1.

2. The cyclic peptide of claim 1, wherein the peptide comprises a lactam bridge.

3. The cyclic peptide of claim 1, wherein the peptide is a stapled peptide.

4. The cyclic peptide of claim 1, wherein the peptide comprises D amino acids.

5. The cyclic peptide of claim 1, wherein the peptide comprises N-methylated amino acids.

6. The cyclic peptide of claim 1, wherein the peptide comprises β

-amino acids.

7. The cyclic peptide of claim 1, wherein the peptide is a peptidomimetic or peptoid.

8. The cyclic peptide of claim 1, wherein the peptide is lipidated.

9. The cyclic peptide of claim 1, wherein the peptide is PEG-ylated.

36. A pharmaceutical formulation comprising a cyclic peptide of claim 1 in a pharmaceutically acceptable carrier.

39. A method of treating a tumor cell or a subject having a tumor cell comprising administering to the tumor cell or the subject the formulation of claim 36.

40. The method of claim 39, wherein the subject has been identified as having a lysine-specific demethylase 1 (LSD1)-overexpressing tumor.

10. A cyclic peptide lysine-specific demethylase 1 inhibitor comprising a sequence at least 90% identical to the peptide sequence of SEQ ID NO:

1, wherein a lactam bridge is formed between a Lys and a Glu residue within the peptide.

11. The cyclic peptide of claim 10, wherein the peptide sequence is SEQ ID NO:

2, and wherein the lactam bridge is formed between Lys2 and Glu14.

12. The cyclic peptide of claim 10, wherein the peptide sequence is SEQ ID NO:

3, and wherein the lactam bridge is formed between LysS and Glu10.

13. The cyclic peptide of claim 10, wherein the peptide sequence is SEQ ID NO:

4, and wherein the lactam bridge is formed between Lys2 and Glu10.

14. The cyclic peptide of claim 10, wherein the peptide sequence is SEQ ID NO:

5, and wherein the lactam bridge is formed between Lys2 and Glu12.

15. The cyclic peptide of claim 10, wherein the peptide sequence is SEQ ID NO:

6, and wherein the lactam bridge is formed between Lys2 and Glu5.

16. The cyclic peptide of claim 10, wherein the peptide sequence is SEQ ID NO:

7, and wherein the lactam bridge is formed between Lys9 and Glu14.

17. -22. (canceled)

23. A cyclic peptide lysine-specific demethylase 1 inhibitor comprising the sequence of H-AX₁TMX₂TARKX₃TX₄GX₅APRKQLA-NH₂, wherein X₁ is K or R;

X₂ is Q, K, or E;

X₃ is S or E;

X₄ is G or E; and

X₅ is K or E, and wherein;

X₁ is K, X₂ is Q, X₃ is 5, X₄ is G, and X₅ is E, and wherein a lactam bridge is formed between X₁ and X₅;

X₁ is K, X₂ is Q, X₃ is E, X₄ is G, and X₅ is K, and wherein a lactam bridge is formed between X₁ and X₃;

X₁ is K, X₂ is Q, X₃ is 5, X₄ is E, and X₅ is K, and wherein a lactam bridge is formed between X₁ and X₄;

X₁ is K, X₂ is E, X₃ is 5, X₄ is G, and X₅ is K, and wherein a lactam bridge is formed between X₁ and X₂;

X₁ is R, X₂ is K, X₃ is E, X₄ is G, and X₅ is K, and wherein a lactam bridge is formed between X₂ and X₃;

or

X₁ is R, X₂ is Q, X₃ is 5, X₄ is G, and X₅ is E, and wherein a lactam bridge is formed between Lys9 and X₅.

24. -35. (canceled)

37. -38. (canceled)

41. -45. (canceled)