Cyclic peptide binder against oncogenic K-Ras

Patent metadata

Field	Value
Publication number	US-10913774-B2
Application number	US-201816031840-A
Country	US
Kind code	B2
Filing date	Jul 10, 2018
Priority date	Mar 11, 2015
Publication date	Feb 9, 2021
Grant date	Feb 9, 2021

Abstract

Cyclic peptides represented by (Formula 1)

selectively bind the oncoprotein K-Ras G12D in vitro and in cellulo, where Z1 and Z2 are each L-propargylglycine (Pm), azidoornithine (OrnN3), or L-azidolysine (Az4), and V1-V2-V3-V4-V5 is an amino acid variable region having a sequence selected from the group consisting of SEQ ID NOs: 1-20.

First claim

We claim:

1. A cyclic peptide represented by Formula I:

wherein:
Z1 and Z2 are each non-naturally occurring amino acids;
V1-V2-V3-V4-V5 is a five amino acid variable region, wherein V1 is L or V, V2 is R, homoR, or guanidinoF, V3 is G, V4 is D, P, E, A, N, or Q, and V5 is guanidinoF or R;
L is a linker moiety; and
B m is an optional group, wherein m is 0 or 1.

2. The cyclic peptide of claim 1 , wherein Z1 and Z2 are not the same.

3. The cyclic peptide of claim 1 , wherein when Z1 is Pra, Z2 is OrnN3 or Az4, when Z1 is OrnN3 or Az4, Z2 is Pra.

4. The cyclic peptide of claim 1 , wherein Z1 is Pra and Z2 is Az4.

5. The cyclic peptide of claim 1 , wherein Z1 is Pra and Z2 is OrnN3.

6. The cyclic peptide of claim 1 , wherein Z1 is Az4 and Z2 is Pra.

7. The cyclic peptide of claim 1 , wherein V1-V2-V3-V4-V5 have a sequence selected from the group consisting of SEQ ID NOs:10-20.

8. The cyclic peptide of claim 1 , wherein V1-V2-V3-V4-V5 is SEQ ID NO: 7, 11, or 16.

9. The cyclic peptide of claim 8 , wherein V1-V2-V3-V4-V5 is SEQ ID NO:16.

10. The cyclic peptide of claim 1 , wherein L is a triazole group.

11. The cyclic peptide of claim 1 , wherein L is 1,4-triazole.

12. The cyclic peptide of claim 1 , wherein Z1 is Pra and Z2 is Az4, and wherein V1-V2-V3-V4-V5 is SEQ ID NO:16.

13. The cyclic peptide of claim 1 , wherein Z1 is Pra and Z2 is Az4, and wherein L is 1,4-triazole.

14. The cyclic peptide of claim 1 , wherein Z1 is Pra and Z2 is Az4, wherein m is 1, wherein B is a combination of a spacer group and a detection tag.

15. The cyclic peptide of claim 1 , wherein Z1 is Pra and Z2 is Az4, wherein m is 1, wherein B is a combination of a spacer group and a detection tag, and wherein the spacer group is PEG and the detection tag is biotin.

16. The cyclic peptide of claim 1 , wherein V1-V2-V3-V4-V5 is SEQ ID NO:16, and wherein L is 1,4-triazole.

17. The cyclic peptide of claim 1 , wherein V1-V2-V3-V4-V5 is SEQ ID NO:16, wherein m is 1, and wherein B is a combination of a spacer group and a detection tag.

18. The cyclic peptide of claim 1 , wherein V1-V2-V3-V4-V5 is SEQ ID NO:16, wherein m is 1, wherein B is a combination of a spacer group and a detection tag, and wherein the spacer group is PEG and the detection tag is biotin.

19. The cyclic peptide of claim 1 , wherein Z1 is Pra and Z2 is Az4, wherein V1-V2-V3-V4-V5 is SEQ ID NO:16, and wherein L is 1,4-triazole.

20. The cyclic peptide of claim 1 , wherein Z1 is Pra and Z2 is Az4, wherein V1-V2-V3-V4-V5 is SEQ ID NO:16, wherein m is 1, and wherein B is a combination of a spacer group and a detection tag.

21. The cyclic peptide of claim 1 , wherein Z1 is Pra and Z2 is Az4, wherein V1-V2-V3-V4-V5 is SEQ ID NO:16, wherein m is 1, wherein B is a combination of a spacer group and a detection tag, and wherein the spacer group is PEG and the detection tag is biotin.

22. The cyclic peptide of claim 1 , wherein Z1 is Pra and Z2 is Az4, wherein V1-V2-V3-V4-V5 is SEQ ID NO:16, wherein L is 1,4-triazole, wherein m is 1, and wherein B is a combination of a spacer group and a detection tag.

23. The cyclic peptide of claim 1 , wherein Z1 is Pra and Z2 is Az4, wherein V1-V2-V3-V4-V5 is SEQ ID NO:16, wherein L is 1,4-triazole, wherein m is 1, wherein B is a combination of a spacer group and a detection tag, and wherein the spacer group is PEG and the detection tag is biotin.

24. The cyclic peptide of claim 1 having the structure:

25. The cyclic peptide of claim 1 , wherein B is conjugated to any group of the cyclic peptide.

26. The cyclic peptide of claim 25 , wherein B is conjugated to the C-terminus of Z2.

27. The cyclic peptide of claim 1 , wherein when m is 1, and wherein B is a spacer group, a detection tag, or a combination of a spacer group and a detection tag.

28. The cyclic peptide of claim 27 , wherein B is a spacer group.

29. The cyclic peptide of claim 27 , wherein the detection tag is a chemical moiety that can be selectively bound.

30. The cyclic peptide of claim 27 , wherein the detection tag is an affinity tag, a fluorescent tag, or a fluorescently labeled affinity tag.

31. The cyclic peptide of claim 27 , wherein the detection tag is an affinity tag selected from the group consisting of biotin, streptavidin, poly-histidine, poly-arginine, FLAG, cyclodextrin, adamantane, and combinations thereof.

32. The cyclic peptide of claim 27 , wherein the spacer group is polyethylene glycol (PEG) or 6-aminohexanoic acid (Ahx).

33. The cyclic peptide of claim 32 , wherein the spacer group includes 2 to 24 PEG units.

34. The cyclic peptide of claim 32 , wherein the spacer group includes 2 to 15 PEG units.

35. The cyclic peptide of claim 32 , wherein the spacer group includes 2 to 10 PEG units.

36. The cyclic peptide of claim 32 , wherein the spacer group includes 2 to 5 PEG units.

37. The cyclic peptide of claim 32 , wherein the spacer group includes 2 to 4 PEG units.

38. The cyclic peptide of claim 32 , wherein the spacer group includes 2 to 3 PEG units.

39. The cyclic peptide of claim 27 , wherein B is a combination of a spacer group and a detection tag.

40. The cyclic peptide of claim 37 , wherein the spacer group is PEG and the detection tag is biotin.

41. A cyclic peptide comprising the structure:

42. The cyclic peptide of claim 1 , wherein the cyclic peptide is conjugated with a moiety.

43. A method of inhibiting K-Ras G12D oncoprotein in a cancer cell expressing K-Ras G12D, the method comprising:
incubating the cancer cell with the cyclic peptide of claim 1 .

44. The method of claim 43 , wherein the cancer cell is pancreatic, colorectal, lung, biliary tract, or ovarian cancer.

45. A method of inhibiting K-Ras G12D oncoprotein in a cancer cell expressing K-Ras G12D, the method comprising:
incubating the cancer cell with the cyclic peptide of claim 42 .

46. The method of claim 45 , wherein the cancer cell is pancreatic, colorectal, lung, biliary tract, or ovarian cancer.

Assignees

• California Inst Of Techn

Inventors

• Henning Ryan K
• Ram Ashwin N
• Das Samir
• Nag Arundhati
• Heath James R

Classifications

• G01N33/57575 Primary

  involving oncogenic proteins · CPC title

• C07K14/82

  Translation products from oncogenes · CPC title

• G01N2333/82

  Translation products from oncogenes · CPC title

• C07K7/06

  having 5 to 11 amino acids · CPC title

• C07K7/64 Primary

  Cyclic peptides containing only normal peptide links · CPC title