Engineered potent cytotoxic stapled BH3 peptides

Patent metadata

Field	Value
Publication number	US-10344064-B2
Application number	US-201615265321-A
Country	US
Kind code	B2
Filing date	Sep 14, 2016
Priority date	Feb 3, 2012
Publication date	Jul 9, 2019
Grant date	Jul 9, 2019

Abstract

Compositions comprising peptide sequences with high cytotoxicity to cancer cell lines are provided. Pharmaceutical compositions comprising peptide sequences with high cytotoxicity to cancer cell lines are provided. A method for treating cancer is provided.

First claim

What is claimed is:

1. A composition comprising an engineered cytotoxic stapled BH3 peptide comprising a fourteen amino acid sequence having a crosslink,
the engineered cytotoxic stapled BH3 peptide comprising the structure of:

wherein the crosslink is between the Xaa 3 residue at position 8 of the fourteen amino acid sequence and the Xaa 5 residue at position 12 of the fourteen amino acid sequence, and Xaa 3 and Xaa 5 are selected from any amino acid.

2. The composition of claim 1 , wherein Xaa 3 and Xaa 5 are α, α-disubstituted 5-carbon olefinic unnatural amino acids and the crosslink is between Xaa 3 and Xaa 5 .

3. The composition of claim 1 , wherein the engineered cytotoxic stapled BH3 peptide is 14, 15, or 16 amino acids in length.

4. The composition of claim 1 further comprising at least one of ABT-737 or ABT-199.

5. The composition of claim 1 further comprising a pharmaceutically acceptable carrier.

6. The composition of claim 5 , wherein the pharmaceutically acceptable carrier includes at least one substance selected from the group consisting of ion exchangers; alumina; aluminum stearate; lecithin; serum proteins; human serum albumin; buffer substances; phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts; electrolytes; protamine sulfate; disodium hydrogen phosphate; potassium hydrogen phosphate; sodium chloride; zinc salts; colloidal silica; magnesium trisilicate; polyvinyl pyrrolidone; cellulose-based substances; polyethylene glycol; sodium carboxymethylcellulose; waxes; polyethylene glycol; starch; lactose; dicalcium phosphate; microcrystalline cellulose; sucrose; dextrose; talc; magnesium carbonate; kaolin; non-ionic surfactants; edible oils; physiological saline; bacteriostatic water; and phosphate buffered saline (PBS).

Assignees

• Univ Princeton

Inventors

• Link A James
• Zhang Siyan

Classifications

• A61K38/12

  Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)} · CPC title

• A61K38/10

  Peptides having 12 to 20 amino acids {(A61K38/043 - A61K38/046 take precedence)} · CPC title

• A61K38/1761

  Apoptosis related proteins, e.g. Apoptotic protease-activating factor-1 (APAF-1), Bax, Bax-inhibitory protein(s)(BI; bax-I), Myeloid cell leukemia associated protein (MCL-1), Inhibitor of apoptosis [IAP] or Bcl-2 · CPC title

• A61K31/635

  having a heterocyclic ring, e.g. sulfadiazine · CPC title

• G01N33/68

  involving proteins, peptides or amino acids {(involving lipoproteins G01N33/92)} · CPC title