Inhibitors of PARP Activity and Uses Thereof

• US 20100323974A1
• Filed: 11/14/2006
• Published: 12/23/2010
• Est. Priority Date: 11/14/2005
• Status: Active Grant

• Current Assignee: Centre National De La Recherche Scientifique
• Original Assignee: Centre National De La Recherche Scientifique
• Inventors: Hamiche, Ali
• Granted Patent: US 9,150,628 B2
• Time in Patent Office: Days
• US Class Current: 514/21.2
• CPC Class Codes: 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
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 14/47 : from mammals

Abstract

The present invention relates to new inhibitors of the nucleic enzyme poly(adenosine 5′-diphospho-ribose) polymerase [“poly(ADP-ribose) polymerase” or “PARP”, which is also sometimes called “PARS” for poly(ADP-ribose) synthetase]. More particularly, the invention relates to the use of PARP inhibitors to prevent and/or treat tissue damage resulting from cell damage or death due to necrosis or apoptosis; neural tissue damage resulting from ischemia and reperfusion injury; neurological disorders and neurodegenerative diseases; to prevent or treat vascular stroke; to treat or prevent cardiovascular disorders; to treat other conditions and/or disorders such as age-related macular degeneration, AIDS and other immune senescence diseases, arthritis, atherosclerosis, cachexia, cancer, degenerative diseases of skeletal muscle involving replicative senescence, diabetes, head trauma, immune senescence, inflammatory bowel disorders (such as colitis and Crohn'"'"'s disease), muscular dystrophy, osteoarthritis, osteoporosis, chronic and acute pain (such as neuropathic pain), renal failure, retinal ischemia, septic shock (such as endotoxic shock), and skin aging; to extend the lifespan and proliferative capacity of cells; to alter gene expression of senescent cells; or to radiosensitize hypoxic tumor cells.

Claims

1. An inhibitor of the nucleic enzyme poly(adenosine 5′

-diphospho-ribose) polymerase [“

poly(ADP-ribose) polymerase (PARP) having a phosphoesterase activity, and comprising an amino acid sequence, which is derived from the C-terminal non-histone domain of a macroH2A histone, optionally fused and/or coupled to at least one heterologous sequence.

2. The inhibitor according to claim 1, wherein the C-terminal non-histone domain of macroH2A histone is selected in the group comprising the C-terminal non-histone domain of human macroH2A1.1 (amino acids 121 to 369 of SEQ ID NO:

1), macroH2A1.2 (amino acids 120 to 371 of SEQ ID NO;

2), and macroH2A2 (amino acids 121 to 372 of SEQ ID NO;

3) histones.

3. The inhibitor according to claim 2, wherein preferably the C-terminal non-histone domain of macroH2A histone is the C-terminal non-histone domain of macroH2A1.1.

4. The inhibitor according to claim 1, wherein said inhibitor comprises an amino acid sequence, which is derived from the C-terminal non-histone domain of a macroH2A histone, and less is than 350 amino acids in length, preferably less than 150 amino acids in length.

5. The inhibitor according to claim 1, wherein said amino acid sequence, which is derived from the C-terminal non-histone domain of a macroH2A histone does not comprise the macroH2A histone fold domain having homology with histone H2A.

6. The inhibitor according to claim 1, wherein the amino acid sequence, which is derived from the non-histone domain of a macroH2A histone comprises the macro domain of a macro H2A histone.

7. The inhibitor according to claim 6, wherein the macro domain of a macroH2A histone is selected in the group comprising the residues 184 to 369, preferably 202 to 369 of human macroH2A1.1 (SEQ ID NO:

1), the residues 183 to 371, preferably 201 to 371 of human macroH2A1.2 (SEQ ID NO;

2), and the residues 184 to 372, preferably 202 to 372 of human macroH2A2 (SEQ ID NO;

3).

8. A nucleic acid encoding for an inhibitor according to claim 1.

9. A vector comprising a nucleic acid according to claim 8.

10. A composition comprising (i) an inhibitor according to claim 1, a nucleic acid or a vector, and (ii) a pharmaceutically acceptable vehicle.

11. Use of an inhibitor according to claim 1, of a nucleic acid or of a vector for the manufacture of a medicament for the prevention or treatment of a subject suffering from a disease associated with PARP activation.

12. The use according to claim 11, wherein the disease associated with PARP activation is selected in the group comprising tissue damage resulting from cell damage or death due to necrosis or apoptosis, neural tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, vascular stroke cardiovascular disorders, age-related macular degeneration, AIDS, immune senescence diseases, arthritis, atherosclerosis, cachexia, cancer, degenerative diseases of skeletal muscle involving replicative senescence, diabetes, head trauma, immune senescence, inflammatory disorders, muscular dystrophy, osteoarthritis, osteoporosis, chronic and/or acute pain, renal failure, retinal ischemia, septic shock, skin aging.