# US 8,748,395 B2 · Cell-permeable peptide inhibitors of the JNK signal transduction pathway

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

- Number: US 8,748,395 B2
- Document ID: US8748395B2
- Status: Granted
- Kind: B2
- Application number: 12/066,657
- Filed: 2006-09-12
- Published: 2009-12-10
- Granted: 2014-06-10
- Earliest claimed: 2006-09-12
- Assignees: Xigen Inflammation Ltd.
- Applicants: Christophe Bonny
- Inventors: Christophe Bonny
- Web page: https://patentgrep.com/patent/US8748395B2

## CPC

- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- C07K 14/005: from viruses
- A61P 7/08: Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock (artificial tears A61P27/04)
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 9/14: Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/16: Central respiratory analeptics
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 27/16: Otologicals
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 31/18: for HIV
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/04: Immunostimulants
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 39/06: Free radical scavengers or antioxidants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 7/08: having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68)
- C07K 14/47: from mammals
- C07K 14/4703: {Inhibitors; Suppressors}
- C07K 16/18: against material from animals or humans
- C12N 7/00: Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00)
- 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)
- C07K 2319/10: containing a tag for extracellular membrane crossing, e.g. TAT or VP22
- C12N 2740/16322: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C12N 2740/16371: Demonstrated in vivo effect
- 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)
- 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)

## Abstract

Protein kinase inhibitors and more specifically inhibitors of the protein kinase c-Jun amino terminal kinase are described. Additionally, JNK inhibitor sequences, chimeric peptides, nucleic acids encoding same as well as pharmaceutical compositions for treating pathophysiologies associated with JNK signaling are described.

## Claims

### Claim 1

A JNK inhibitor sequence consisting of a D-enantiomeric amino acid sequence of SEQ ID NO: 2.

### Claim 2 (depends on 1)

The JNK inhibitor sequence of claim 1, wherein the JNK inhibitor sequence binds c-jun amino terminal kinase (JNK).

### Claim 3 (depends on 2)

The JNK inhibitor sequence of claim 2, wherein the JNK inhibitor sequence inhibits the activation of at least one JNK targeted transcription factor when the JNK inhibitor sequence is present in a JNK expressing cell.

### Claim 4 (depends on 3)

The JNK inhibitor sequence of claim 3, wherein the JNK targeted transcription factor is selected from the group consisting of c-Jun, ATF2, and Elkl.

### Claim 5 (depends on 4)

The JNK inhibitor sequence of claim 4, wherein the JNK inhibitor sequence alters a JNK effect when the peptide is present in a JNK expressing cell.

### Claim 6 (depends on 1)

A pharmaceutical composition comprising the JNK inhibitor sequence according to claim 1 and a pharmaceutically acceptable carrier.

### Claim 7 (depends on 6)

A method of treating a pathophysiology associated with activation of JNK in a subject, the method comprising administering the pharmaceutical composition of claim 6, wherein the pathophysiology is a malignancy of the lung, breast, lymphoid, gastrointestinal, genito-urinary tract, adenocarcinomas, colon cancers, renal-cell carcinoma, prostate cancer, non-small cell carcinoma of the lung, cancer of the small intestine, cancer of the esophagus, leukemia, Bcr-Abl oncogenic transformations, psoriasis, pemphigus vulgaris, Behcet's syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, post-dialysis syndrome, rheumatoid arthritis, acquired immune deficiency syndrome, vasculitis, septic shock, restenosis, hearing loss, ear trauma, ischemia, stroke, reperfusion injuries, hypoxia, inflammation, arterial hypertension, cardiac hypertrophy, arteriosclerotic lesions, ischemia/reperfusion injuries, hypothermia, hyperthermia, stroke, brain trauma, spinal cord injury, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, cardiovascular disease, osteoporosis, myopathies, cardiomyopathies or graft injection.

### Claim 8 (depends on 7)

The method of claim 7, wherein the pharmaceutical composition is administered by an administration route selected from the group consisting of intraperitoneal, nasal, intravenous, oral and patch delivery.

### Claim 9 (depends on 1)

A kit comprising the JNK inhibitor sequence according to claim 1.

### Claim 10

A chimeric peptide consisting of a first domain and a second domain linked by a covalent bond, the first domain comprising a trafficking sequence, and the second domain consisting of a JNK inhibitor sequence according to SEQ ID NO: 2,
wherein the trafficking sequence comprises the D-enantiomeric amino acid sequence of SEQ ID NO: 5, 6, 7 or 8 or a sequence sharing at least about 90% sequence identity with the D-enantiomeric SEQ ID NOs: 5 or 6.

### Claim 11 (depends on 10)

The chimeric peptide of claim 10,
wherein the first domain is linked to the C-terminal end of the second domain.

### Claim 12 (depends on 11)

The peptide of claim 11, wherein the trafficking sequence comprises the amino acid sequence of SEQ ID NO: 5 or 6.

### Claim 13 (depends on 12)

The peptide of claim 12, wherein the trafficking sequences comprises the D-enantiomeric amino acid sequence of SEQ ID NO: 6.

### Claim 14 (depends on 13)

The peptide of claim 13, wherein the trafficking sequence directs nuclear localization of the peptide.

### Claim 15 (depends on 11)

The peptide of claim 11, wherein the peptide comprises an amino acid sequence selected from the group consisting of the D-enantiomeric amino acid sequences of SEQ ID NOs: 11 and 12.

### Claim 16 (depends on 15)

The peptide of claim 15, wherein the peptide comprises the D-enantiomeric amino acid sequence of SEQ ID NO: 11.

### Claim 17 (depends on 10)

A pharmaceutical composition comprising the chimeric peptide according to claim 10 and a pharmaceutically acceptable carrier.

### Claim 18 (depends on 17)

A method of treating a pathophysiology associated with activation of JNK in a subject, the method comprising administering the pharmaceutical composition of claim 17, wherein the pathophysiology is a malignancy of the lung, breast, lymphoid, gastrointestinal, genito-urinary tract, adenocarcinomas, colon cancers, renal-cell carcinoma, prostate cancer, non-small cell carcinoma of the lung, cancer of the small intestine, cancer of the esophagus, leukemia, Bcr-Abl oncogenic transformations, psoriasis, pemphigus vulgaris, Behcet's syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, post-dialysis syndrome, rheumatoid arthritis, acquired immune deficiency syndrome, vasculitis, septic shock, restenosis, hearing loss, ear trauma, ischemia, stroke, reperfusion injuries, hypoxia, inflammation, arterial hypertension, cardiac hypertrophy, arteriosclerotic lesions, ischemia/reperfusion injuries, hypothermia, hyperthermia, stroke, brain trauma, spinal cord injury, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, cardiovascular disease, osteoporosis, myopathies, cardiomyopathies or graft injection.

### Claim 19 (depends on 18)

The method of claim 18, wherein the pharmaceutical composition is administered by an administration route selected from the group consisting of intraperitoneal, nasal, intravenous, oral and patch delivery.

### Claim 20 (depends on 10)

A kit comprising the chimeric peptide according to claim 10.

### Claim 21

A chimeric peptide consisting of a first domain and a second domain linked by a covalent bond, the first domain comprising a trafficking sequence, and the second domain consisting of a JNK inhibitor sequence,
wherein the trafficking sequence comprises the D-enantiomeric amino acid sequence of SEQ ID NO: 5, 6, 7 or 8 or a sequence sharing at least about 90% sequence identity with the D-enantiomeric SEQ ID NOs: 5 or 6, and wherein the JNK inhibitor sequence consists of the D retro inverso amino acid sequence according to NH2-Xnb-DQXXXXXXXLXLTTPR-Xna-Xnb-COOH (SEQ ID NO: 4), wherein n for Xna in SEQ ID NO: 4 is 0 each Xnb is selected independently, Xnb may not comprise a serine or threonine residue at its C-terminus, and when n for Xnb in SEQ ID NO: 4 is 1, Xnb may not be a serine or threonine residue.