Methods of modulating cellular homeostatic pathways and cellular survival

Patent metadata

Field	Value
Publication number	US-10716828-B2
Application number	US-59847908-A
Country	US
Kind code	B2
Filing date	May 2, 2008
Priority date	May 2, 2007
Publication date	Jul 21, 2020
Grant date	Jul 21, 2020

Abstract

The invention provides composition and therapeutic, methods for modulating homeostatic pathways that are useful in treatment, and prevention of diabetes, diabetes associated disorders, metabolic disorders and cancer.

First claim

What is claimed is:

1. A method of treating diabetes, the method comprising administering to a human subject in need thereof a peptide, wherein the peptide is less than 100 amino acids in length and comprises the amino acid sequence of any one of the following:
a) NLWAAQRYGRELRX 1 MSDX 2 FVDSFKK (SEQ ID NO: 18);
b) NLWAAQRYGRELRX 1 XSDX 2 FVDSFKK (SEQ ID NO: 47);
c) NLWAAQRYGRELRX 1 MZDX 2 FVDSFKK (SEQ ID NO: 21);
d) NLWAAQRYGRELRX 1 XZDX 2 FVDSFKK (SEQ ID NO: 51);
e) NLWAAQRYGRELRX 1 MDDX 2 FVDSFKK (SEQ ID NO: 22);
f) NLWAAQRYGRELRX 1 XDDX 2 FVDSFKK (SEQ ID NO: 49);
g) NLWAAQRYGRELRX 1 BSDX 2 FVDSF (SEQ ID NO: 64);
h) LWAAQRYGRELRX 1 BSDX 2 FVDSFK (SEQ ID NO: 70);
i) LWAAQRYGRELRX 1 BSDX 2 FVDSF (SEQ ID NO: 71); or
j) WAAQRYGRELRX 1 BSDX 2 FVDSF (SEQ ID NO: 72);

wherein X 1 and X 2 are independently any non-natural amino acid;
wherein Z is phosphoserine;
wherein X is norleucine; and
wherein B is β-alanine.

2. The method of claim 1 , wherein said X 1 and X 2 are either S-N-(9-Fluorenylmethyl carbamate)-2-(4′-pentenyl) alanine (S5) or aminobutyric acid.

3. The method of claim 1 , wherein X 1 and X 2 of said peptide are S-N-(9-Fluorenylmethyl carbamate)-2-(4′-pentenyl) alanine (S5), said peptide includes an intermolecular cross-link between X 1 and X 2 , and said peptide, if it includes a serine between X 1 and X 2 , is phosphorylated on the serine.

4. The method of claim 1 , wherein said peptide consists of the amino acid sequence of any one of the following:
a) NLWAAQRYGRELRX 1 MSDX 2 FVDSFKK (SEQ ID NO: 18);
b) NLWAAQRYGRELRX 1 XSDX 2 FVDSFKK (SEQ ID NO: 47);
c) NLWAAQRYGRELRX 1 MZDX 2 FVDSFKK (SEQ ID NO: 21);
d) NLWAAQRYGRELRX 1 XZDX 2 FVDSFKK (SEQ ID NO: 51);
e) NLWAAQRYGRELRX 1 MDDX 2 FVDSFKK (SEQ ID NO: 22);
f) NLWAAQRYGRELRX 1 XDDX 2 FVDSFKK (SEQ ID NO: 49);
g) NLWAAQRYGRELRX 1 BSDX 2 FVDSF (SEQ ID NO: 64);
h) LWAAQRYGRELRX 1 BSDX 2 FVDSFK (SEQ ID NO: 70);
i) LWAAQRYGRELRX 1 BSDX 2 FVDSF (SEQ ID NO: 71); or
j) WAAQRYGRELRX 1 BSDX 2 FVDSF (SEQ ID NO: 72);

wherein X 1 and X 2 are independently any non-natural amino acid;
wherein Z is phosphoserine;
wherein X is norleucine; and
wherein B is β-alanine.

5. The method of claim 1 , wherein X 1 and X 2 of said peptide are S-N-(9-Fluorenylmethyl carbamate)-2-(4′-pentenyl) alanine (S5), and said peptide includes an intermolecular cross-link between X 1 and X 2 .

6. The method of claim 4 , wherein X 1 and X 2 of said peptide are S-N-(9-Fluorenylmethyl carbamate)-2-(4′-pentenyl) alanine (S5), and said peptide includes an intermolecular cross-link between X 1 and X 2 .

7. The method of claim 1 , wherein the peptide comprises the amino acid sequence of any one of the following:
a) NLWAAQRYGRELRX 1 MSDX 2 FVDSFKK (SEQ ID NO: 18);
b) NLWAAQRYGRELRX 1 XSDX 2 FVDSFKK (SEQ ID NO: 47);
c) NLWAAQRYGRELRX 1 MZDX 2 FVDSFKK (SEQ ID NO: 21);
d) NLWAAQRYGRELRX 1 XZDX 2 FVDSFKK (SEQ ID NO: 51);
e) NLWAAQRYGRELRX 1 MDDX 2 FVDSFKK (SEQ ID NO: 22);
f) NLWAAQRYGRELRX 1 XDDX 2 FVDSFKK (SEQ ID NO: 49);

wherein X 1 and X 2 are independently any non-natural amino acid;
wherein Z is phosphoserine; and
wherein X is norleucine.

8. The method of claim 1 , wherein the peptide comprises the amino acid sequence of NLWAAQRYGRELRX 1 XDDX 2 FVDSFKK (SEQ ID NO: 49), wherein X 1 and X 2 are independently any non-natural amino acid; and wherein X is norleucine.

9. The method of claim 4 , wherein the peptide consists of the amino acid sequence of any one of the following:
a) NLWAAQRYGRELRX 1 MSDX 2 FVDSFKK (SEQ ID NO: 18);
b) NLWAAQRYGRELRX 1 XSDX 2 FVDSFKK (SEQ ID NO: 47);
c) NLWAAQRYGRELRX 1 MZDX 2 FVDSFKK (SEQ ID NO: 21);
d) NLWAAQRYGRELRX 1 XZDX 2 FVDSFKK (SEQ ID NO: 51);
e) NLWAAQRYGRELRX 1 MDDX 2 FVDSFKK (SEQ ID NO: 22);
f) NLWAAQRYGRELRX 1 XDDX 2 FVDSFKK (SEQ ID NO: 49);
wherein X 1 and X 2 are independently any non-natural amino acid;
wherein Z is phosphoserine; and
wherein X is norleucine.

10. The method of claim 4 , wherein the peptide consists of the amino acid sequence of NLWAAQRYGRELRX 1 XDDX 2 FVDSFKK (SEQ ID NO: 49), wherein X 1 and X 2 are independently any non-natural amino acid; and wherein X is norleucine.

11. The method of claim 7 , wherein X 1 and X 2 of said peptide are S-N-(9-Fluorenylmethyl carbamate)-2-(4′-pentenyl) alanine (S5), and said peptide includes an intermolecular cross-link between X 1 and X 2 .

12. The method of claim 8 , wherein X 1 and X 2 of said peptide are S-N-(9-Fluorenylmethyl carbamate)-2-(4′-pentenyl) alanine (S5), and said peptide includes an intermolecular cross-link between X 1 and X 2 .

13. The method of claim 9 , wherein X 1 and X 2 of said peptide are S-N-(9-Fluorenylmethyl carbamate)-2-(4′-pentenyl) alanine (S5), and said peptide includes an intermolecular cross-link between X 1 and X 2 .

14. The method of claim 10 , wherein X 1 and X 2 of said peptide are S-N-(9-Fluorenylmethyl carbamate)-2-(4′-pentenyl) alanine (S5), and said peptide includes an intermolecular cross-link between X 1 and X 2 .

Assignees

• Danial Nika N
• Walensky Loren D
• Bird Gregory
• Korsmeyer Susan R
• Dana Farber Cancer Inst Inc

Inventors

• Danial Nika N
• Walensky Loren D
• Bird Gregory
• Korsmeyer Stanley J

Classifications

• A61K38/1761 Primary

  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

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title