Peptidomimetic macrocycles

• US 10,300,109 B2
• Filed: 11/11/2016
• Issued: 05/28/2019
• Est. Priority Date: 09/22/2009
• Status: Active Grant

• Current Assignee: Aileron Therapeutics Inc.
• Original Assignee: Aileron Therapeutics Inc.
• Inventors: Nash, Huw M., Kapeller-Libermann, Rosana, Han, Jia-Wen, Sawyer, Tomi K., Noehre, Justin, Kawahata, Noriyuki
• Primary Examiner(s): Audet, Maury A
• Application Number:
  US15/349,478
• Publication Number:
  US 20170266254A1
• Time in Patent Office: 928 Days
• Field of Search: None
• 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 38/12 Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C A61K38/043 - A61K38/046 take precedence
• 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: 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 14/00 Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
• CPC Class Codes: C07K 7/50 Cyclic peptides containing at least one abnormal peptide link
• CPC Class Codes: C07K 7/64 Cyclic peptides containing only normal peptide links

Abstract

Disclosed are peptidomimetic macrocycles comprising a helix, such as an alpha helix, and methods of using such macrocycles for the treatment of disease such as cancer. In other aspects, the peptidomimetic macrocycle comprises an α,α-disubstituted amino acid, or may comprise a crosslinker linking the α-positions of at least two amino acids or at least one of said two amino acids may be an α,α-disubstituted amino acid. Further included is the targeting of components of the Wnt signaling pathway such as the Tcf4-/3-catenin complex.

Claims

1. A peptidomimetic macrocycle comprising the amino acid sequence chosen from the group consisting of SEQ ID NOS:

1, 27, 43, and 44, wherein the amino acid sequence comprises a crosslinker linking the α

-positions of at least two amino acids that are at least three amino acids apart within the peptidomimetic macrocycle, wherein the crosslinker is an alkylene or alkenylene crosslinker.

2. The peptidomimetic macrocycle of claim 1, wherein the peptidomimetic macrocycle comprises a helix.

3. The peptidomimetic macrocycle of claim 1, wherein the peptidomimetic macrocycle comprises an α

-helix.

4. The peptidomimetic macrocycle of claim 1, wherein the peptidomimetic macrocycle comprises an α

,α

a-disubstituted amino acid.

5. The peptidomimetic macrocycle of claim 1, wherein at least one of said two amino acids is an α

,α

-disubstituted amino acid.

6. The peptidomimetic macrocycle of claim 1, wherein the peptidomimetic macrocycle has the formula: