Ras inhibitory peptides and uses thereof

• US 10,533,039 B2
• Filed: 05/21/2015
• Issued: 01/14/2020
• Est. Priority Date: 05/21/2014
• Status: Active Grant

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Verdine, Gregory L., McGee, John Hanney
• Primary Examiner(s): Russel, Jeffrey E.
• Application Number:
  US15/312,958
• Publication Number:
  US 20170240604A1
• Time in Patent Office: 1,699 Days
• 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 38/16 Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof enzyme inhibitors A61K38/005
• CPC Class Codes: A61K 38/22 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• CPC Class Codes: C07K 14/00 Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
• CPC Class Codes: C07K 14/4703 Inhibitors; Suppressors
• CPC Class Codes: C07K 14/575 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695
• CPC Class Codes: C07K 14/82 Translation products from oncogenes
• 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
• CPC Class Codes: C12N 15/1037 Screening libraries presented on the surface of microorganisms, e.g. phage display, E. coli display
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention provides peptides comprising a sequence of X₋₆X₋₅X₋₄X₋₃X₋₂X₋₁X₁PX₃X₄PX₆X₇PGX₁₀X₁₁AX₁₃X₁₄X₁₅X₁₆LX₁₈X₁₉X₂₀X₂₁X₂₂X₂₃LX₂₅X₂₆ YLX₂₉X₃₀X₃₁X₃₂ (SEQ ID NO: 13) wherein the amino acids X₋₆, X₋₅, X₋₄, X₋₃, X₋₂, X₋₁, X₁, X₃, X₄, X₆, X₇, X₁₀, X₁₁, X₁₃, X₁₄, X₁₅, X₁₆, X₁₈, X₁₉, X₂₀, X₂₁, X₂₂, X₂₅, X₂₆, X₂₉, X₃₀, X₃₁, and X₃₂ are as defined herein. The present invention further provides pharmaceutical compositions comprising the peptides and methods of using the peptides for treating proliferative diseases such as cancer which are associated with Ras. Also provided are methods of screening a library of peptide dimers using a peptide dimer display technology.

Claims

1. A peptide comprising a sequence of:

2. The peptide of claim 1, wherein the peptide is a first peptide that associates with a second peptide to form a peptide dimer that binds to a target protein, wherein the target protein is Ras, a Ras mutant, Myc/Max, RalA, Beta catenin, YAP/TEAD, or NEMO/Iκ

B kinase.

3. A method of treating a disease or condition associated with Ras in a subject in need thereof comprising administering a peptide of claim 1 to the subject.

4. The method of claim 3, wherein the disease associated with Ras is a proliferative disease.

5. The method of claim 3, wherein the proliferative disease is cancer.

6. The method of claim 3, wherein the disease associated with Ras is CFC syndrome, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, Legius syndrome, Neurofibromatosis type 1, Noonan syndrome, or Noonan syndrome with multiple lentigines (formerly LEOPARD syndrome).

7. A host cell comprising a peptide of claim 1.

8. A peptide dimer comprising a first peptide associated with a second peptide, wherein the first and second peptides each independently comprise a peptide sequence of:

9. The peptide dimer of claim 8, wherein the peptide dimer is a homodimer.

10. The peptide dimer of claim 8, wherein the peptide dimer is a heterodimer.