Peptides and peptidomimetics having anti-proliferative activity and/or that augment nucleic acid damaging agents or treatments

• US 20040248783A1
• Filed: 01/17/2003
• Published: 12/09/2004
• Est. Priority Date: 01/17/2002
• Status: Active Grant

• Current Assignee: CanBas Co., Ltd.
• Original Assignee: CanBas Co., Ltd.
• Inventors: Kawabe, Takumi, Kobayashi, Hidetaka
• Granted Patent: US 6,995,135 B2
• Time in Patent Office: Days
• US Class Current: 514/12
• CPC Class Codes: A61K 38/00 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 Class Codes: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 51/088 conjugates with carriers being peptides, polyamino acids or proteins antibodies A61K51/10
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 5/06078 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/06191 containing heteroatoms different from O, S, or N
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68

Abstract

This invention provides compounds including peptides and peptidomimetics that can be used to treat cell proliferative disorders, such as those associated with benign and malignant tumor cells. While the invention is not limited to any particular mechanism, the compounds of the invention appear to function at least in part by inhibiting G2 cell cycle checkpoint. Thus, invention compounds can be used to inhibit cell growth alone or be used in combination with a nucleic acid damaging treatment to inhibit cell growth.

Claims

1. A contiguous peptide or peptidomimetic sequence comprising the following structure:

P1, P2, P3, P4, P5, P6 (SEQ ID NO;

1) or P6, P5, P4, P3, P2, P1 (SEQ ID NO;

2);

wherein P1 is Cha, Nal(2), (Phe-2,3,4,5,6-F), (Phe-3,4,5F), (Phe-4CF3), an amino acid that occupies a similar side chain space, or any amino acid with one or two aromatic, piperidine, pyrazine, pyrimidine, piperazine, morpholine or pyrimidine group(s), or one indole, pentalene, indene, naphthalene, benzofuran, benzothiophene, quinoline, indoline, chroman, quinoxaline, quinazoline group in the side chain;

wherein P2 is Cha, Nal(2), (Phe-2,3,4,5,6-F), (Phe-3,4,5F), (Phe-4CF3), Bpa, Phe₄NO₂, an amino acid that occupies a similar side chain space, or any amino acid with one or two aromatic, piperidine, pyrazine, pyrimidine, piperazine, morpholine or pyrimidine group(s), or one indole, pentalene, indene, naphthalene, benzofuran, benzothiophene, quinoline, indoline, chroman, quinoxaline, or quinazoline group in the side chain;

wherein P3, P4, P5 are any amino acid, or wherein one or more of P3, P4, P5 is a simple carbon chain such that the distance between P2 and P6 is about the same as the distance when each of P3, P4, P5 are amino acids;

wherein P6 is Bpa, Phe₄NO₂, any one amino acid and Tyr, any one amino acid and Phe, any amino acid, or nothing.

2. The peptide or peptidomimetic sequence of claim 1, wherein the amino acid having a simple carbon chain is 11-aminoundecanoic acid, 10-aminodecanoic acid, 9-aminononanoic acid, 8-aminocaprylic acid, 7-aminoheptanoic acid, 6-aminocaproic acid, or a similar structure with one or more unsaturated carbon bonds.

3. The peptide or peptidomimetic sequence of claim 1, wherein the any one amino acid is Ser.

4. The peptide or peptidomimetic sequence of claim 1, wherein P4 is Trp.

5. The peptide or peptidomimetic sequence of claim 1, wherein the amino acid that occupies a similar side chain space is Tyr or Phe.

25. The peptide or peptidomimetic sequence of any of claims 1, 6, 11, 16 to 20 or 22, wherein one or more residues is l-type.

26. The peptide or peptidomimetic sequence of any of claims 1, 6, 11, 16 to 20 or 22, wherein one or more residues is d-type.

28. The peptide or peptidomimetic sequence of any of claims 1, 6, 11, 16 to 20 and 22 to 24, wherein the sequence inhibits proliferation of a cell.

29. The peptide or peptidomimetic sequence of any of claims 1, 6, 11, 16 to 20 and 22 to 24, wherein the sequence abrogates cell cycle G2 checkpoint of a cell.

30. The peptide or peptidomimetic sequence of any of claims 1, 6, 11, 16 to 20 and 22 to 24, wherein the sequence has a length from about 6 to about 12, 10 to about 20, 18 to about 25, 25 to about 100, 25 to about 200, or 50 to about 300 residues in length.

31. A composition comprising the peptide or peptidomimetic sequence of any of claims 1, 6, 11, 16 to 20 and 22 to 24 and a nucleic acid damaging agent.

32. A composition comprising the peptide or peptidomimetic sequence of any of claims 1, 6, 11, 16 to 20 and 22 to 24 and an anti-proliferative agent.

33. A pharmaceutical composition comprising the peptide or peptidomimetic sequence of any of claims 1, 6, 11, 16 to 20 and 22 to 24.

34. A pharmaceutical composition comprising the peptide or peptidomimetic sequence of any of claims 1, 6, 11, 16 to 20 and 22 to 24 and a nucleic acid damaging agent or an anti-proliferative agent.

35. A kit comprising the peptide or peptidomimetic sequence of any of claims 1, 6, 11, 16 to 20 and 22 to 24 and instructions for use.

36. The kit of claim 35, wherein the instructions for use include instructions for inhibiting cell proliferation in combination with a nucleic acid damaging treatment.

37. The kit of claim 35, further comprising a nucleic acid damaging agent.

38. The kit of claim 35, further comprising an anti-proliferative agent.

39. A method of inhibiting proliferation of a cell, comprising contacting a cell with an amount of a peptide or peptidomimetic of any of claims 1, 6, 11, 16 to 20 and 22 to 24 sufficient to inhibit proliferation of the cell.

40. The method of claim 39, further comprising contacting the cell with a nucleic acid damaging agent or exposing the cell to a nucleic acid damaging treatment.

41. The method of claim 40, wherein the cell is a cultured cell, or is present in a subject.

42. A method of increasing sensitivity of a cell to a nucleic acid damaging agent or treatment, comprising contacting the cell with an amount of a peptide or peptidomimetic of any of claims 1, 6, 11, 16 to 20 and 22 to 24 sufficient to increase sensitivity of the cell to a nucleic acid damaging agent or treatment.

43. The method of claim 42, further comprising contacting the cell with a nucleic acid damaging agent or exposing the cell to a nucleic acid damaging treatment.

44. The method of claim 57, wherein the cell is a cultured cell, or is present in a subject.

45. A method of increasing nucleic acid damage to a cell, comprising contacting a cell with an amount of a peptide or peptidomimetic of any of claims 1, 6, 11, 16 to 20 and 22 to 24 sufficient to increase nucleic acid damage of the cell.

46. The method of claim 45, further comprising contacting the cell with a nucleic acid damaging agent or exposing the cell to a nucleic acid damaging treatment.

47. The method of claim 45, wherein the cell is a cultured cell, or is present in a subject.

48. A method of treating a cell proliferative disorder, comprising administering to a subject having or at risk of having a cell proliferative disorder an amount of peptide or peptidomimetic of any of claims 1, 6, 11, 16 to 20 and 22 to 24 effective to treat the cell proliferative disorder.

49. The method of claim 48, wherein at least a part of the cells comprising the cell proliferative disorder is located in blood, breast, lung, thyroid, head or neck, brain, lymph, gastrointestinal tract, nasopharynx, genito-urinary tract, bladder, kidney, pancreas, liver, bone, muscle, or skin.

50. The method of claim 48, wherein the peptide or peptidomimetic is administered locally, regionally or systemically.

51. The method of claim 48, wherein the cell proliferative disorder comprises a benign or malignant solid or liquid tumor.

52. The method of claim 51, wherein the tumor is metastatic or non-metatstaic.

53. The method of claim 51, wherein the solid tumor comprises a sarcoma or carcinoma.

54. The method of claim 51, wherein the liquid tumor comprises a hematopoietic cancer.

55. The method of claim 54, wherein the hematopoietic cancer comprises a myeloma, lymphoma or leukemia.

56. The method of claim 51, wherein the treatment results in improving the subjects condition.

57. The method of claim 56, wherein the improvement comprises decreased cell proliferation, decreased numbers of cells, inhibiting increased cell proliferation, inhibiting increases in numbers of cells, increased apoptosis, or decreased survival, of at least a portion of the cells comprising the cell proliferative disorder.

58. The method of claim 54, further comprising administering a nucleic acid damaging agent, a nucleic acid damaging treatment, an anti-proliferative agent, or an anti-proliferative treatment to the subject.

59. The method of claim 58, wherein the agent or treatment comprises a drug, radiation, a radioisotope, environmental shock.

60. The method of claim 59, wherein the drug comprises a chemotherapeutic drug.

61. The method of claim 58, wherein the drug comprises 5-fluorouracil (5-FU), rebeccamycin, adriamycin (ADR), bleomycin (Bleo), pepleomycin, a cisplatin derivative, or camptotecin (CPT).

62. The method of claim 61, wherein the cisplatin derivative comprises cisplatin (CDDP) or oxaliplatin.

63. The method of claim 59, wherein the radioisotope comprises I¹³¹, I¹²⁵, ⁹⁰Y, ¹⁷⁷Lu, ²¹³Bi, or ²¹¹At.

64. The method of claim 59, wherein the radiation comprises UV radiation, IR radiation, or alpha-, beta- or gamma-radiation.

65. The method of claim 59, wherein the environmental shock comprises hyperthermia.

6. A contiguous peptide or peptidomimetic sequence comprising the following structure:

7. The peptide or peptidomimetic sequence of claim 6, wherein the amino acid having a simple carbon chain is 11-aminoundecanoic acid, 10-aminodecanoic acid, 9-aminononanoic acid, 8-aminocaprylic acid, 7-aminoheptanoic acid, 6-aminocaproic acid, or a similar structure with one or more unsaturated carbon bonds.

8. The peptide or peptidomimetic sequence of claim 6, wherein the any one amino acid is Ser.

9. The peptide or peptidomimetic sequence of claim 6, wherein P4 is Trp.

10. The peptide or peptidomimetic sequence of claim 6, wherein the amino acid that occupies a similar side chain space is Tyr or Phe.

11. A contiguous peptide or peptidomimetic sequence comprising the following structure:

12. The peptide or peptidomimetic sequence of claim 11, wherein the amino acid having a simple carbon chain is aminoundecanoic acid or 8-aminocaprylic acid.

13. The peptide or peptidomimetic sequence of claim 11, wherein the any one amino acid is Ser.

14. The peptide or peptidomimetic sequence of claim 11, wherein P4 is Trp.

15. The peptide or peptidomimetic sequence of claim 11, wherein the amino acid that occupies a similar side chain space is Tyr or Phe.

16. A contiguous peptide or peptidomimetic sequence comprising the following structure:

P1, P2, P3, P4, P5, P6 (SEQ ID NO;

21) or P6, P5, P4, P3, P2, P1 (SEQ ID NO;

22);

wherein P1 is Cha, Nal(2), (Phe-2,3,4,5,6-F), (Phe-3,4,5F), (Phe-4CF3), Bpa, Phe₄NO₂, Tyr, or Phe;

wherein P2 is Cha, Nal(2), (Phe-2,3,4,5,6-F), (Phe-3,4,5F), (Phe-4CF3), Bpa, Phe₄NO₂, Tyr, or Phe;

wherein P3 is Ser, Arg, Cys, Pro, or Asn;

wherein P4 is Trp;

wherein P5 is Ser, Arg, or Asn;

or

wherein P3, P4, P5 is a single aminoundecanoic acid or a single 8-aminocaprylic acid; and

wherein P6 is Bpa, Phe₄NO₂, (Ser-Tyr), or (Ser-Phe).

17. A contiguous peptide or peptidomimetic sequence comprising the following structure:

18. A contiguous peptide or peptidomimetic sequence comprising the following structure:

19. A contiguous peptide or peptidomimetic sequence comprising the following structure:

20. A contiguous peptide or peptidomimetic sequence comprising the following structure:

21. The peptide or peptidomimetic sequence of claim 20, wherein the any amino acid is Ser, or Pro.

22. A contiguous peptide or peptidomimetic sequence comprising the following structure:

23. A contiguous peptide or peptidomimetic sequence comprising the following structure:

27. The peptide or peptidomimetic sequence of any of claims 23 or 24, wherein a d-residue is substituted with an l-residue.

24. A contiguous peptide or peptidomimetic sequence comprising the following structure: