Stabilized p53 peptides and uses thereof

• US 8,889,632 B2
• Filed: 01/31/2008
• Issued: 11/18/2014
• Est. Priority Date: 01/31/2007
• Status: Active Grant

• Current Assignee: Dana-Farber Cancer Institute, President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: Dana-Farber Cancer Institute, President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Bernal, Federico, Walensky, Loren D., Verdine, Gregory L., Korsmeyer, Stanley J.
• Primary Examiner(s): GUDIBANDE, SATYANARAYAN R
• Application Number:
  US12/525,123
• Publication Number:
  US 20100168388A1
• Time in Patent Office: 2,483 Days
• Field of Search: None
• US Class Current: 514/21.4
• 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: 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: C07K 1/113 without change of the primary structure
• CPC Class Codes: C07K 14/4746 p53

Abstract

Cross-linked peptides related to human p53 and bind to HMD2 or a family member of HDM2 useful for promoting apoptosis, e.g., in the treatment of and identifying therapeutic agents that binding to HMD2 or a family member of HDM2.

Claims

1. A modified polypeptide of Formula (I)

2. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, wherein the modified polypeptide or the pharmaceutically acceptable salt thereof binds to HDM2.

3. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, wherein each R₃ is independently an alkenylene containing a single double bond, and both R₁ and R₂ are H.

4. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, wherein the modified polypeptide or the pharmaceutically acceptable salt thereof does not have a net negative charge at pH 7.

5. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 4, wherein the modified polypeptide or the pharmaceutically acceptable salt thereof comprises at least one amino acid that has a positive charge at pH 7, wherein the at least one amino acid is at either:

(a) amino terminal to Leu₁ or the amino acid substituted for Leu₁ or (b) carboxy terminal to Asn₁₆ or the amino acid substituted for Asn₁₆.

6. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, wherein R₁ and R₂ are each independently H or C₁-C₆ alkyl.

7. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, wherein each R₃ is independently C₈ alkylene.

8. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, wherein each R₃ is independently C₁₁ alkylene.

9. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, wherein each R₃ is independently alkenylene.

10. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, wherein each R₃ is independently C₈ alkenylene.

11. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, wherein each R₃ is independently C₁₁ alkenylene.

12. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, wherein each R₃ is independently a straight chain alkylene, alkenylene, or alkynylene.

13. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, further comprising a copolymer of lactic and glycolic acid.

14. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, further comprising an amino-terminal fatty acid.

15. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, further comprising a biotin moiety.

16. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, wherein the modified polypeptide or the pharmaceutically acceptable salt thereof is capable of being transported through a cell membrane.

17. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, further comprising a PEG, a tat protein, an affinity label, a targeting moiety, a fatty acid-derived acyl group, a biotin moiety, or a fluorescent probe.

18. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 17, wherein the fluorescent probe is fluorescein or rhodamine.

19. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 17, wherein the fluorescent probe is linked via a thiocarbamate or carbamate linkage to the modified polypeptide or the pharmaceutically acceptable salt thereof.

20. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, wherein each R₁ and R₂ are independently C₁-C₃ alkyl.

21. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, wherein both R₁ and R₂ are methyl.

22. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, further comprising a targeting moiety.

23. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, wherein the modified polypeptide or the pharmaceutically acceptable salt thereof binds to HDMX.

24. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, wherein the modified polypeptide or the pharmaceutically acceptable salt thereof binds to HDMX and HDM2.

25. The modified polypeptide or the pharmaceutically acceptable salt thereof of claim 1, 2, 3, 6, 7, 8, 9, 10, 11, 12, 20, 21, 23 or 24, wherein z is 1.