Substrate-mimetic AKT inhibitor

Patent metadata

Field	Value
Publication number	US-9896668-B2
Application number	US-201615251572-A
Country	US
Kind code	B2
Filing date	Aug 30, 2016
Priority date	Dec 7, 2006
Publication date	Feb 20, 2018
Grant date	Feb 20, 2018

Abstract

Disclosed herein is a species of peptide and non-peptide inhibitors of Akt, an oncogenic protein. Beginning with a residue of Akt target substrate GSK-3, the functional domains of the GSK-3 residue were characterized. Functionally homologous non-peptide groups were substituted for the amino acids of the GSK-3 creating a hybrid peptide-non-peptide and non-peptide compounds capable of binding to Akt. The non-peptide compounds show increased stability and rigidity compared to peptide counterparts and are less susceptible to degradation. The bound non-peptide compounds exhibit an inhibitory effect on Akt, similar to peptide-based Akt inhibitors.

First claim

What is claimed is:

1. A method of inhibiting AKT in at least one cell, comprising contacting a cell with a composition, wherein the composition comprises the formula:
Y 1 —Y 2 —X 1 —Y 3 —F—X 2   (I);

wherein Y 1 is acetyl, G-A-P—, acetylated G-A-P, G-R—P, or acetylated G-R—P—;
wherein Y 2 is R or A;
where Y 2 is A when Y 1 is G-R—P or acetylated G-R—P;

wherein X 1 is -T-T-,

where X 3 is N-benzyl acetamide;
where X 4 is hydrogen, methyl, or phenyl;
where X 5 is hydrogen, phenyl, or napthyl;

wherein Y 3 is S or V;
wherein X 2 is aminobenzyl, benzyl,

wherein G is glycine, R is arginine, P is proline, T is threonine, W is tryptophan, F is phenylalanine, H is histidine, V is valine, A is alanine, C is cysteine, and N is asparagine.

2. The method of claim 1 , wherein the wherein X 1 is aminobenzoic acid.

3. The method of claim 1 , wherein Y 3 is V.

4. The method of claim 1 , wherein Y 1 is G-R—P, or acetylated G-R—P—.

5. The method of claim 4 , wherein X 1 is

where X 4 is hydrogen;
where X 5 is hydrogen or phenyl;
wherein Y 3 is V; and
wherein X 2 is aminobenzyl, benzyl, or

6. The method of claim 4 , wherein X 1 is

where X 4 is hydrogen;
where X 5 is hydrogen or phenyl; and
wherein X 2 is aminobenzyl or benzyl.

7. The method of claim 6 , wherein Y 3 is V.

8. The method of claim 1 , wherein the at least one cell is an ovarian cancer cell, breast cancer cell, thyroid cancer cell, or colon cancer cell.

9. A method of inhibiting AKT in at least one cell, comprising contacting a cell with a composition, wherein the composition comprises the formula:
X 1 —X 2 —V—F-end cap  (II)

wherein X 1 is H 2 N—C(NH)NH—, H 2 N—C(NH)NH—CH 2 —CH 2 —, H 2 N—C(NH)NH—(CH 2 ) 4 —C(O)—;
wherein X 2 is aminobenzoic acid or a substituted amino benzoic acid;
where the substituted amino benzoic acid has a functional substituent comprising N-benzyl-acetamide, N-tert-butyl acetamide, or propyl-benzene;

wherein V is valine and F is phenylalanine; and
wherein the end cap is benzyl or aminobenzyl.

10. The method of claim 9 , wherein X 1 is H 2 N—C(NH)NH—(CH 2 ) 4 —C(O)—, X 2 is the substituted amino benzoic acid, and N-benzyl-acetamide or propyl-benzene is the functional substituent.

11. The method of claim 10 , wherein the functional substituent is N-benzyl-acetamide.

12. The method of claim 9 , wherein the at least one cell is an ovarian cancer cell, breast cancer cell, thyroid cancer cell, or colon cancer cell.

13. A method of inhibiting AKT in at least one cell, comprising contacting a cell with a composition, wherein the composition comprises the formula:
X 1 —X 2 —V—X 3 -[end cap] 2   (III)

wherein X 1 is H 2 N—C(O)NH—,
wherein X 2 is (CH 2 ) 3 CH(NHC(O)CH 3 )C(O)CH 2 —, (CH 2 ) 2 , CH 2 C(O)—, CH 2 C(O)NH—;
wherein V is amino benzoic acid, a substituted amino benzoic acid, or phenyl;
wherein X 3 is

and
wherein the end cap is benzyl, methyl, methyl napthyl, para-methylbenzonitrile, or para-ispropylbenzyl.

14. The method of claim 13 , wherein V is amino benzoic acid.

15. The method of claim 14 , wherein X 3 is

16. The method of claim 14 , wherein the end cap is para-methylbenzonitrile or para-ispropylbenzyl.

17. The method of claim 13 , wherein the at least one cell is an ovarian cancer cell, breast cancer cell, thyroid cancer cell, or colon cancer cell.

Assignees

• Univ South Florida
• Univ Yale

Inventors

• Sebti Said M
• Cheng Jin Q
• Hamilton Andrew D
• Kayser Bricker Katherine

Classifications

• C07D209/04

  Indoles; Hydrogenated indoles · CPC title

• C07K5/08

  Tripeptides · CPC title

• C07K7/06

  having 5 to 11 amino acids · CPC title

• C07D209/14

  Radicals substituted by nitrogen atoms, not forming part of a nitro radical · CPC title

• A61K31/132

  having two or more amino groups, e.g. spermidine, putrescine · CPC title