Non-membrane disruptive P53 activating stapled peptides

Patent metadata

Field	Value
Publication number	US-11319344-B2
Application number	US-201615550766-A
Country	US
Kind code	B2
Filing date	Feb 15, 2016
Priority date	Feb 13, 2015
Publication date	May 3, 2022
Grant date	May 3, 2022

Abstract

The present invention relates to non-membrane disruptive and p53 activating stapled peptides, as well as methods of treatment of cancer involving the use of these peptides. In one embodiment, the peptide comprises or consist of the amino acid sequence of TSFXaa1EY-WXaa3LLXaa2, where Xaa1 is (R)-2-(7′-octenyl)alanine or derivative thereof, or is (R)-2-(4′-pentenyl)alanine or derivative thereof; and Xaa2 and Xaa3 are independently any type of amino acid or modified amino acid. In another embodiment, the peptide comprising or consisting of the amino acid sequence of TSFXaa1EYW Xaa3LLXaa2ENXaa5, wherein Xaa1 and Xaa3 are any type of amino acid or modified amino acid; Xaa2 is S, or P, or (S)-2-(4′-pentenyl)alanine or a derivative of (S)-2-(4′-pentenyl)alanine; and wherein Xaa5 is F or Y.

First claim

What is claimed is:

1. A peptide comprising or consisting of the amino acid sequence of:
TSFXaa 1 EYWXaa 3 LLXaa 2 (SEQ ID NO: 27)
wherein
Xaa 4 is (R)-2-(7′-octenyl)alanine, or (S)-2-(4′-pentenyl)alanine, or (R)-2-(4′-pentenyl)alanine, or (S)-2-(7′-octenyl)alanine;
Xaa 3 is (R)-2-(4′-pentenyl)alanine or (S)-2-(4′-pentenyl)alanine;
Xaa 2 is independently any type of amino acid,
wherein each amino acid residue is optionally substituted with one or more halogens, and wherein the peptide is a cross-linked peptide with a cross-linker to connect a first amino acid Xaa 1 to a second amino acid Xaa 2 ; or wherein the peptide is a cross-linked peptide with a cross-linker to connect a first amino acid Xaa 1 to a second amino acid Xaa 3 .

2. The peptide of claim 1 , wherein Xaa 2 is S, or P, or (S)-2-(4′-pentenyl)alanine.

3. The peptide of claim 1 , wherein the peptide comprises the formula:

wherein:
R 1 is —C(OH)CH 3 [T];
R 2 is —CH 2 OH [S];
R 3 is benzyl [F];
R 4 is —CH 3 ;
R 5 is —(CH 2 ) 2 C(O)OH [E];
R 6 is —CH 2 -Phenyl-OH [Y];
R 7 is the side chain of Trp, wherein C 6 of Trp is substituted with a hydrogen or a halogen and/or wherein Trp is independently an L or D optical isomer;
R 8 is —CH 3 ;
R 9 and R 10 are —CH 2 CH(CH 3 ) 2 [L];
R 11 is independently the side chain of any amino acid;
R is alkyl, alkenyl, or alkynyl.

4. A peptide comprising or consisting of the amino acid sequence of:
TSFXaa 1 EYW Xaa 3 LLXaa 2 ENXaa 5 (SEQ ID NO: 28)

wherein
Xaa 1 and Xaa 3 are any type of amino acid;
Xaa 2 is S, or P, or (S)-2-(4′-pentenyl)alanine;
wherein Xaa 5 is F or Y,
wherein each amino acid residue is optionally substituted with one or more halogens, and wherein the peptide is a cross-linked peptide with a cross-linker to connect a first amino acid Xaa 1 to a second amino acid Xaa 2 ; or wherein the peptide is a cross-linked peptide with a cross-linker to connect a first amino acid Xaa 1 to a second amino acid Xaa 3 .

5. The peptide of claim 4 , wherein Xaa 3 is N, or A, or (R)-2-(4′-pentenyl)alanine or (S)-2-(4′-pentenyl)alanine; and wherein if Xaa 3 is N, Xaa 1 is not A and/or Xaa 2 is not S; and/or wherein Xaa 1 is (R)-2-(7′-octenyl)alanine, or (S)-2-(4′-pentenyl)alanine or (R)-2-(4′-pentenyl)alanine, or (S)-2-(7′-octenyl)alanine.

6. The peptide of claim 4 , wherein the peptide comprises the formula:

or

the peptide of claim 4 , wherein the peptide comprises the formula:

wherein:
R 1 is —C(OH)CH 3 [T];
R 2 is —CH 2 OH [S];
R 3 is benzyl [F];
R 4 is —CH 3 ;
R 5 is —(CH 2 ) 2 C(O)OH [E];
R 6 is —CH 2 -Phenyl-OH [Y];
R 7 is the side chain of Trp, wherein C 6 of Trp is substituted with a hydrogen or a halogen and/or wherein Trp is independently an L or D optical isomer;
R 8 is independently the side chain of any amino acid;
R 9 and R 10 are —CH 2 CH(CH 3 ) 2 [L];
R 11 is —CH 3 or —CH 2 OH [S] or —(CH 2 ) 3 —, wherein —(CH 2 ) 3 — is attached to the backbone nitrogen atom to form proline [P];
R is alkyl, alkenyl, or alkynyl;
R 12 is —(CH 2 ) 2 C(O)OH [E];
R 15 is —CH 2 C(O)NH 2 [N]:
R 16 is independently either benzyl [F] or —CH 2 -Phenyl-OH [Y].

7. The peptide of claim 1 , wherein the N-terminus or C-terminus of the peptide is bound to a covalent linker, wherein a sequence Z n is attached to the unbound end of the linker; wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and wherein Z is a molecule with a single localized positive charge; and/or wherein n is 1 or 2 or 3; and/or wherein Z is arginine [R] or lysine [K]; and/or wherein the linker and the sequence Z n comprise the sequence of Ac-KK-Ahx (acetylated-Lys-Lys-aminohexanoic acid) or Ac-RRR-Ahx (acetylated-Arg-Arg-Arg-aminohexanoic acid).

8. The peptide of claim 1 , wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 5 and SEQ ID NO: 6.

9. The peptide according to claim 1 , wherein W at position 7 of the peptide is modified by addition of one or more halogens independently selected from the group consisting of F, Cl, Br, and I; and/or wherein the peptide comprises 1, 2, 3, 4, or 5 halogens; and/or wherein W at position 7 is modified by addition of a halogen at position C 6 of W and/or wherein W is independently an L or D optical isomer.

10. A pharmaceutical composition comprising a peptide according to claim 1 .

11. The pharmaceutical composition according to claim 10 , wherein the pharmaceutical composition comprises a further therapeutic compound.

12. The pharmaceutical composition of claim 11 , wherein the further therapeutic compound is an apoptosis promoting compound.

13. The peptide of claim 4 , wherein the N-terminus or C-terminus of the peptide is bound to a covalent linker, wherein a sequence Z n is attached to the unbound end of the linker; wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and wherein Z is a molecule with a single localized positive charge; and/or
wherein n is 1 or 2 or 3; and/or
wherein Z is arginine [R] or lysine [K]; and/or
wherein the linker and the sequence Z n comprise the sequence of Ac-KK-Ahx (acetylated-Lys-Lys-aminohexanoic acid) or Ac-RRR-Ahx (acetylated-Arg-Arg-Arg-aminohexanoic acid).

14. A pharmaceutical composition comprising a peptide according to claim 4 .

15. The pharmaceutical composition according to claim 14 , wherein the pharmaceutical composition comprises a further therapeutic compound.

16. The pharmaceutical composition of claim 15 , wherein the further therapeutic compound is an apoptosis promoting compound.

17. The peptide of claim 4 , wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10.

18. The peptide according to claim 4 , wherein W at position 7 of the peptide is modified by addition of one or more halogens independently selected from the group consisting of F, Cl, Br, and I; and/or wherein the peptide comprises 1, 2, 3, 4, or 5 halogens; and/or wherein W at position 7 is modified by addition of a halogen at position C6 of W and/or wherein W is independently an L or D optical isomer.

19. A method of treating or preventing cancer in a patient comprising administering a pharmaceutically effective amount of the peptide of claim 1 .

20. The method according to claim 19 wherein the method comprises the administration of one or more further therapeutic agents to the patient, wherein administration is simultaneous, sequential or separate.

21. The method of claim 19 , wherein the cancer is selected front a group consisting of gastric cancer, colon cancer, lung cancer, breast cancer, bladder cancer, neuroblastoma, melanoma, and leukemia.

22. The method of claim 19 , wherein the patient suffering or suspected to suffering from cancer comprises a tumor with p53 deficient tumor cells or p53 genes comprising a

Assignees

• Agency Science Tech & Res

Inventors

• Tan Yaw Sing
• Brown Christopher John
• Verma Chandra S
• Ferrer Gago Fernando Jose
• Lane David P
• Joseph Thomas

Classifications

• C07K7/06

  having 5 to 11 amino acids · CPC title

• A61K38/08

  Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)} · CPC title

• A61K38/10

  Peptides having 12 to 20 amino acids {(A61K38/043 - A61K38/046 take precedence)} · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title