# US 2013/0156753 A1 · THE cAMP/PKA/HDAC5 PATHWAY AND USES THEREOF

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- Number: US 2013/0156753 A1
- Document ID: US20130156753A1
- Status: Published application
- Kind: A1
- Application number: 13/809,789
- Filed: 2011-07-31
- Published: 2013-06-20
- Earliest claimed: 2010-07-13
- Assignees: University of Rochester
- Inventors: Zheng-gen Jin
- Web page: https://patentgrep.com/patent/US20130156753A1

## CPC

- A61K 39/39533: {against materials from animals}
- A61K 31/352: condensed with carbocyclic rings, e.g. methantheline {(cannabinoids A61K31/658)}
- A61K 31/7076: containing purines, e.g. adenosine, adenylic acid
- A61K 31/7088: Compounds having three or more nucleosides or nucleotides
- A61K 31/7105: Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
- A61K 38/10: Peptides having 12 to 20 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- C07K 16/40: against enzymes
- C12N 15/1137: {against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138)}
- C12Y 207/11011: cAMP-dependent protein kinase (2.7.11.11)
- G01N 33/5061: {Muscle cells}
- G01N 33/573: for enzymes or isoenzymes
- C12N 2310/14: interfering nucleic acids [NA]
- G01N 2333/98: acting on amide bonds in linear amides (3.5.1)
- G01N 2440/14: phosphorylation
- G01N 2500/04: Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
- G01N 2500/10: involving cells
- G01N 2800/325: Heart failure or cardiac arrest, e.g. cardiomyopathy, congestive heart failure
- 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
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Y: ENZYMES
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The present invention provides novel uses of the cAMP/PKA/HDAC5 pathway for the treatment and prevention of myopathies.

## Claims

### Claim 1

A method of inhibiting HDAC5 activity in a cell, comprising contacting the cell with an agent that increases cAMP/PKA/HDAC5 pathway activity in the cell, wherein the cell is subjected to stress.

### Claim 2 (depends on 1)

The method of claim 1, wherein the HDAC 5 activity is selected from the group consisting of nuclear export and interaction between HDAC5 and 14-3-3 protein.

### Claim 3

(canceled)

### Claim 4 (depends on 1)

The method of claim 1, wherein inhibition of HDAC5 activity represses MEF2-dependent gene expression or inhibits cardiac fetal gene expression.

### Claim 5

(canceled)

### Claim 6 (depends on 1)

The method of claim 1, wherein the agent is selected from the group consisting of a protein kinase A activator and an agent that increases cAMP levels.

### Claim 7 (depends on 6)

The method of claim 6, wherein the protein kinase A activator is selected from the group consisting of forskolin and cAMP.

### Claim 8

(canceled)

### Claim 9 (depends on 6)

The method of claim 6, wherein the agent that increases cAMP levels is selected from the group consisting of a cAMP-specific PDE IV inhibitor, a Gs activator, a PDE II inhibitor and a beta-adrenergic agonist.

### Claim 10 (depends on 1)

The method of claim 1, wherein the cell is a myocyte.

### Claim at position 11

-12. (canceled)

### Claim 13

A method of preventing cardiac myopathy or of preventing or delaying the occurrence of heart failure in a subject, comprising administering to the subject an agent that increases cAMP/PKA/HDAC5 pathway activity.

### Claim 14 (depends on 13)

The method of claim 13, wherein the agent is a protein kinase A activator or an agent that increases cAMP levels.

### Claim 15 (depends on 14)

The method of claim 14, wherein the protein kinase A activator is selected from the group consisting of forskolin and cAMP.

### Claim 16

(canceled)

### Claim 17 (depends on 14)

The method of claim 14, wherein the agent that increases cAMP levels is selected from the group consisting of a cAMP-specific PDE IV inhibitor, a Gs activator, a PDE II inhibitor and a beta-adrenergic agonist.

### Claim at position 17

-22. (canceled)

### Claim 23

A method of treating heart failure comprising administering to the subject an agent that decreases cAMP/PKA/HDACS pathway activity.

### Claim 24 (depends on 23)

The method of claim 23, wherein the agent that decreases cAMP/PKA/HDAC5 pathway activity is selected from the group consisting of an agent that inhibits binding of HDAC5 to PKA, an agent that inhibits phosphorylation of HDAC5 at Ser280 by PKA, an antibody that selectively binds the PKA binding site of HDAC5, an antibody that selectively binds the HDAC5 binding site of PKA, a peptide.

### Claim at position 20

-27. (canceled)

### Claim 28 (depends on 24)

The method of claim 24, wherein the peptide comprises the amino acid sequence of SEQ ID NO: 2 or a fragment thereof.

### Claim 29

A method of treating heart failure in a subject comprising administering to the subject an agent that inhibits HDAC5-mediated transcriptional repression of MEF2.

### Claim 30 (depends on 29)

The method of claim 29, wherein the agent is selected from the group consisting of an anti-HDAC5 antibody, an HDAC5 inhibitor, a peptide that inhibits HDAC-5 mediated transcriptional repression of MEF2, an antisense nucleic acid that inhibits HDAC5 mediated transcriptional repression of MEF2, an siRNA that inhibits HDAC5 mediated transcriptional repression of MEF2, or a microRNA that inhibits HDAC5 mediated transcriptional repression of MEF2.

### Claim at position 24

-33. (canceled)

### Claim 34

A method of identifying a compound that inhibits cardiac myopathy via the cAMP/PKA/HDAC5 pathway comprising:
a) contacting a cardiomyocyte with a test compound, wherein the cardiac myocyte is subjected to stress; and
b) measuring phosphorylation of HDAC5 at Ser280, wherein an increase in phosphorylation indicates that the test compound inhibits cardiac myopathy via the cAMP/PKA/HDAC5 pathway.

### Claim 35 (depends on 34)

The method of claim 34, further comprising one or more of the steps of
a) measuring the size of the cardiomyocyte, a decrease in size indicating that the test compound inhibits cardiac myopathy and
b) measuring nuclear export of HDAC5, wherein a decrease in nuclear export indicates that the test compound inhibits cardiac myopathy.

### Claim 36

(canceled)

### Claim 37

A method of identifying a compound that inhibits cardiac myopathy via the cAMP/PKA/HDAC5 pathway comprising:
a) contacting a cardiomyocyte with a test compound, wherein the cardiac myocyte is subjected to stress; and
b) measuring the association of HDAC5 with 14-3-3 protein, a decrease in the association between HDAC5 and 14-3-3 indicating that the test compound inhibits cardiac myopathy via the cAMP/PKA/HDAC5 pathway.

### Claim 38 (depends on 37)

The method of claim 37, further comprising one or more of the steps of
a) measuring the size of the cardiomyocyte, a decrease in size indicating that the test compound inhibits cardiac myopathy, and
b) measuring nuclear export of HDAC5, wherein a decrease in nuclear export indicates that the test compound inhibits cardiac myopathy.

### Claim 39

(canceled)

### Claim 40

A method of identifying a compound that inhibits the binding of HDAC5 to PKA comprising:
a) contacting HDAC5 with a test compound in the presence of PKA; and
b) detecting binding of HDAC5 to PKA, a decrease in binding compared to a control indicating that the test compound inhibits binding of HDAC5 to PKA.

### Claim 41

A method of identifying a compound that inhibits binding of HDAC5 to PKA comprising:
a) contacting a cell that comprises HDAC5, PKA and a construct containing an MEF2 regulatory region operatively linked to a nucleic acid encoding luciferase with a test compound; and
b) detecting the level of luciferase activity, an increase in luciferase activity indicating that the compound inhibits binding of HDAC5 to PKA.

### Claim 42

A method of identifying a compound that inhibits HDAC5-mediated transcriptional repression of MEF2 comprising:
a) contacting a cell with a test compound; and
b) detecting the level of expression of MEF2-dependent gene(s), wherein an increase in expression of MEF2 dependent genes as comparted to control indicates that the test compound is a compound that inhibits HDAC5-mediated transcriptional repression of MEF2.