STABILIZED SOS1 PEPTIDES

• US 20160046671A1
• Filed: 03/14/2014
• Published: 02/18/2016
• Est. Priority Date: 03/15/2013
• Status: Active Grant

• Current Assignee: Dana-Farber Cancer Institute
• Original Assignee: Dana-Farber Cancer Institute
• Inventors: LESHCHINER, Elizaveta, WALENSKY, Loren D.
• Granted Patent: US 10,087,215 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• 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: C07K 14/47 from mammals
• CPC Class Codes: C07K 14/705 Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68

Abstract

Provided herein are polypeptides containing stabilized therapeutic peptides related to KRAS guanidine exchange factor (SOS1). Also provided are compositions containing these polypeptides and methods of using such peptides in the treatment of cancer that includes administering to a subject one of the polypeptides. This disclosure relates to structurally stabilized therapeutic peptides related to KRAS guanidine exchange factor (SOS1), and methods of using such peptides in the treatment of cancer.

Claims

1. An internally cross-linked polypeptide comprising the amino acid sequence A₀B₀C₀D₀E₀F₀G₀ A₁B₁C₁D₁E₁F₁G₁ A2B2 (SEQ ID NO:

1) wherein;

wherein

A₀ is F or a conservative substitution;

B₀ is F or a conservative substitution;

C₀ is G or a conservative substitution;

D₀ is I or a conservative substitution;

E₀ is Y or a conservative substitution;

F₀ is L or a conservative substitution;

G₀ is T or a conservative substitution;

A₁ is N or a conservative substitution;

B₁ is I or a conservative substitution;

C₁ is L or a conservative substitution;

D₁ is K or a conservative substitution;

E₁ is T or a conservative substitution;

F₁ is E or a conservative substitution;

G₁ is E or a conservative substitution;

A₂ is G or a conservative substitution;

B₂ is N or a conservative substitution;

the side chains of two amino acids separated by two or six amino acids are replaced by an internal staple;

the side chains of three amino acids are replaced by internal staples and/or an internal stitch;

the side chains of four amino acids are replaced by internal staples, internal stiches, or a combination of internal staples and stiches;

or

the side chains of at least four amino acids are replaced by internal staples, internal stiches, or a combination of internal staples and stiches.

2. The internally cross-linked peptide of claim 1 selected from:

FFGIYLTNILKTEEGN (SEQ ID NO;

2);

FFGIYLTNILKTEEGNRR (SEQ ID NO;

3);

RRFFGIYLTNILKTEEGN (SEQ ID NO;

4);

FFGIYXTNILKTEEGNPELVRR (SEQ ID NO;

5);

RRFFGIYLTNILKTEEGNPELV (SEQ ID NO;

6);

FFGIYLTNILKTEEGNPELV(SEQ ID NO;

7);

FFGIYLTNILKTEEGNR (SEQ ID NO;

8) RFFGIYLTNILKTEEGN (SEQ ID NO;

9);

FFGIYXTNILKTEEGNPELVR (SEQ ID NO;

10);

RFFGIYLTNILKTEEGNPELV (SEQ ID NO;

11),

wherein the side chains of two amino acids separated by two or six amino acids are replaced by an internal staple;

the side chains of three amino acids are replaced by internal staples and/or an internal stitch;

the side chains of four amino acids are replaced by internal staples, internal stiches, or a combination of internal staples and stiches;

or

the side chains of at least four amino acids are replaced by internal staples, internal stiches, or a combination of internal staples and stiches

3. The cross-linked peptide of claim 1, wherein the amino acid sequence is (SEQ ID NO:

2).

4. The cross-linked peptide of claim 1, wherein the internal staple replacing the side chains of the two amino acids separated by two or six amino acids comprises an internal staple selected from Table 1.

5. The cross-linked peptide of claim 1, wherein the internal staple replacing the side chains of the two amino acids is between B₀ and F₀ or between E₀ and B₁.

6. The cross-linked peptide of claim 1, wherein the side chain of one amino acid is replaced by Formula I or Formula II:

7. The cross-linked peptide of claim 1, wherein the internal staples and/or the internal stitch replacing the side chains of the three amino acids comprise:

an internal stitch selected from Table 1;

at least two internal staples;

or

a combination of at least one internal staple and an internal stitch.

10. The cross-linked peptide of claim 7, wherein the internal stitch replaces the side chain of a first amino acid and a second and a third amino acid thereby cross-linking the first amino acid to the second and third amino acid via an internal cross-link, wherein the first and second amino acid are separated by two, three, or six amino acids, the first and the third amino acids are separated by two, three, or six amino acids, and the second and third amino acids are distinct amino acids.

11. The cross-linked peptide of claim 10, wherein the internal stitch replacing the side chains of the three amino acids cross-links a pair of amino acids separated by two, three, or six amino acids.

12. The cross-linked peptide of claim 1, wherein the side chains of the four amino acids are replaced by two distinct internal staples.

13. The cross-linked peptide of claim 12, wherein a first of the two distinct internal staples cross-links a first pair of amino acids separated by two, three, or six amino acids, and a second of the at least two distinct internal staples cross-links a second pair of amino acids separated by two, three, or six amino acids.

14. A pharmaceutical composition, comprising the cross-linked peptides of claim 1.

15. The pharmaceutical composition of claim 14, comprising a medicament for the treatment of cancer.

16. A method for treat cancer comprising administering to patient in need thereof the cross-linked polypeptide of claim 1.

17. The method of claim 16 wherein the patient harbors a mutant RAS protein.

18. The method of claim 17 wherein the mutant RAS protein is KRAS.

8. (canceled)

9. (canceled)