# US 2010/0168162 A1 · Selective inhibitors of akt and methods of using same

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2010/0168162 A1
- Document ID: US20100168162A1
- Status: Published application
- Kind: A1
- Application number: 12/645,313
- Filed: 2009-12-22
- Published: 2010-07-01
- Earliest claimed: 2008-04-25
- Assignees: Burnham Institute for Medical Research
- Inventors: Ze'ev Ronai; Maurizio Pellecchia; Gary Chiang
- Web page: https://patentgrep.com/patent/US20100168162A1

## CPC

- A61K 31/415: 1,2-Diazoles
- A61K 31/47: Quinolines; Isoquinolines
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 215/227: only one oxygen atom which is attached in position 2
- C07D 307/46: Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 471/04: Ortho-condensed systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention describes an improved method for screening compounds for activity in inhibiting the enzymatic activity of Akt1 protein kinase, also known as Protein Kinase B, an enzyme that is believed to play a key role in the inhibition of apoptosis and thus in the etiology of cancer and other conditions, including neurodegenerative diseases. In general, the method comprises: (1) providing a plurality of compounds suspected of having Akt1 kinase inhibitory activity; (2) modeling the docking of each of the plurality of the compounds with a target binding site derived from the crystal structure of a ternary complex involving Akt1, a nonhydrolyzable ATP analogue, and a peptide substrate derived from a physiological AKT substrate such that the protein active site is defined including those residues within a defined distance from the nonhydrolyzable ATP analogue; (3) ranking the docked compounds by goodness of fit; (4) further selecting compounds from compounds high ranked by goodness of fit in docking by using one or more screening criteria; (5) optionally, visually analyzing structures of compounds selected in step (4) to remove any compounds with improbable docking geometry; and (6) experimentally testing the selected compounds from step (4) or step (5), if step (5) is performed, to determine their inhibitory activity against Akt1 in order to select compounds with Akt1 inhibitory activity. The invention also encompasses pharmaceutical compositions including compounds whose inhibitory activity against Akt1 is discovered by the screening method, as well as methods of use of the pharmaceutical compositions to treat cancer and other conditions.

## Claims

### Claim 1

Compound 2 of Formula (II):
and analogs, derivatives and pharmaceutically acceptable salts thereof.

### Claim 2 (depends on 1)

The analogs of Compound 2 of Formula (II) according to claim 1, wherein the analogs are selected from compounds 83G10, 98C11, 103F6, 83H2 and 101G9 identified in FIG. 15.

### Claim 3

A pharmaceutical composition comprising:
a. Compound 2 of Formula (II) and analogs, derivatives and pharmaceutically acceptable salts thereof; and
b. a pharmaceutically acceptable carrier.

### Claim 4 (depends on 3)

The pharmaceutical composition of claim 3 wherein the composition is effective to inhibit Akt1 kinase activity.

### Claim 5 (depends on 4)

The pharmaceutical composition of claim 4 wherein the composition has an IC50 of from less than about 100 μM.to less than about 5 μM.

### Claim 6 (depends on 3)

The pharmaceutical composition of claim 3 wherein the composition is effective to inhibit NFkB activity.

### Claim 7 (depends on 6)

The pharmaceutical composition of claim 6 wherein the composition has an IC50 of from less than about 100 μM.to less than about 5 μM.

### Claim 8

A method of treating cancer comprising administering a therapeutically effective amount of Compound 2 of Formula (II) and analogs, derivatives and pharmaceutically acceptable salts and pharmaceutical compositions thereof.

### Claim 9 (depends on 8)

The method of claim 8 wherein the cancer comprises melanoma.

### Claim 10

A method of treating conditions characterized by dysregulation of apoptosis and neurogenerative conditions comprising administering a therapeutically effective amount of Compound 2 of Formula (II) and analogs, derivatives and pharmaceutically acceptable salts and pharmaceutical compositions thereof.

### Claim 11

A method for decreasing AKT activity in a patient having increased AKT activity or expression, comprising administering a therapeutically effective amount of Compound 2 of Formula (II) and analogs, derivatives and pharmaceutically acceptable salts and pharmaceutical compositions thereof.

### Claim 12 (depends on 11)

The method of claim 11 wherein the patient is selected from the group consisting of a human, mouse, rat, dog, cat, sheep, horse, cow, pig, goat, chicken, turkey, duck, and goose.

### Claim 13 (depends on 11)

The method of claim 11 wherein said administration is effective to reduce or prevent one or more symptoms of said increased AKT activity.

### Claim 14

A method for decreasing NFkB activity in a patient having increased NFkB activity or expression, comprising administering a therapeutically effective amount of Compound 2 of Formula (II) and analogs, derivatives and pharmaceutically acceptable salts and pharmaceutical compositions thereof.

### Claim 15 (depends on 14)

The method of claim 14 wherein the patient is selected from the group consisting of a human, mouse, rat, dog, cat, sheep, horse, cow, pig, goat, chicken, turkey, duck, and goose.

### Claim 16 (depends on 14)

The method of claim 14 wherein said administration is effective to reduce or prevent one or more symptoms of said increased NFkB activity.

### Claim 17

A kit comprising an amount of Compound 2 of Formula (II) and analogs, derivatives and pharmaceutically acceptable salts and pharmaceutical compositions thereof along with instructions for administering the same to a patient on a label or package insert.