PARKIN LIGASE ACTIVATION METHODS AND COMPOSITIONS

• US 20160160205A1
• Filed: 12/07/2015
• Published: 06/09/2016
• Est. Priority Date: 12/05/2014
• Status: Active Grant

• Current Assignee: Nysnobio Ireland Dac
• Original Assignee: An2h Discovery Limited
• Inventors: Johnston, Jennifer
• Granted Patent: US 10,155,936 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• 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 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: 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
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 27/16 Otologicals
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 2319/42 : containing a HA(hemagglutinin)-tag
• CPC Class Codes: C07K 2319/95 : containing a motif/fusion for degradation (ubiquitin fusions, PEST sequence)
• CPC Class Codes: C12N 9/93 : Ligases (6)
• CPC Class Codes: C12Y 603/02019 : Ubiquitin-protein ligase (6.3.2.19), i.e. ubiquitin-conjugating enzyme
• CPC Class Codes: G01N 2800/28 : Neurological disorders

Abstract

The present invention is directed to methods and compositions for activating a Parkin ligase by administering to a subject in need thereof a therapeutically effective amount of a compound that disrupts at least one Parkin ligase zinc finger. The present invention is also directed to methods of treating and/or reducing the incidence of diseases or conditions related to the activation of Parkin ligase.

Claims

1. A method of activating a Parkin ligase, comprising administering to a subject in need thereof a therapeutically effective amount of a compound that disrupts at least one Parkin ligase zinc finger, wherein the compound can coordinate with a zinc ion, and/or bind or react with a cysteine.

2. The method of claim 1, wherein the activated Parkin ligase suppresses the growth of one or more tumors and/or prevents metastasis of one or more tumors.

3. The method of claim 1, wherein the activated Parkin ligase provides dopamine neuron protection.

4. The method of claim 2, wherein the compound has one or more functions selected from the group consisting of eliminating damaged mitochondria, increasing cell viability during cellular stress, decreasing tumor transformation and mitigating alpha-synuclein in cells.

5. The method of claim 2, wherein the subject has been diagnosed with cancer.

6. The method of claim 5, wherein the cancer is glioblastoma, small cell lung carcinoma, breast cancer or prostate cancer.

7. The method of claim 3, wherein the subject has been diagnosed with a neuro-degenerative disease.

8. The method of claim 7, wherein the neuro-degenerative disease is Parkinson'"'"'s disease, dementia, Amyotrophic lateral sclerosis (ALS) and Huntington'"'"'s disease.

9. The method of claim 8, wherein the dementia is dementia with Lewy bodies (DLB), multiple system atrophy (MSA) or Progressive supranuclear palsy (PSP).

10. The method of claim 1, wherein the compound that can coordinate to a zinc ion is a monodentate, bidentate, or tridentate ligand.

11. The method of claim 10, wherein the compound that can coordinate to a zinc ion substantially disrupts the structure of at least one zinc finger in a Parkin ligase.

12. The method of claim 11, wherein the amino acid residues of at least one zinc finger corresponds to or aligns within one or more domains selected from the group consisting R0 amino acids 141-216, IBR amino acids 328-377, and R2 amino acids 415-465 of human Parkin Ligase.

13. The method of claim 12, wherein at least one zinc finger comprises four cysteine residues.

14. The method of claim 1, wherein Parkin ligase activation alters ubiquitination.

15. The method of claim 1, wherein the compound is an alkylator, oxidant, Michael acceptor, another unsaturated structure and/or has a disulfide.

16. The method of claim 15, wherein the compound substantially disrupts the structure of at least one zinc finger in the Parkin ligase.

17. The method of claim 16, wherein the amino acid residues of at least one zinc finger corresponds to or aligns within one or more domains selected from the group consisting R0 amino acids 141-216, IBR amino acids 328-377, and R2 amino acids 415-465 of human Parkin Ligase.

18. The method of claim 17, wherein the zinc finger comprises four cysteine residues.

19. The method of claim 1, wherein activating the Parkin ligase treats or reduces the incidence of one or more diseases or ailments selected from the group consisting of Alzheimer'"'"'s Dementia, Parkinson'"'"'s disease, Huntington Disease, Amyotrophic Lateral Sclerosis (ALS), Freidreich'"'"'s ataxia, Spinocerebellar Ataxia, Multiple Systems Atrophy, PSP, Tauopathy, Diffuse Lewy Body Disease, Lewy Body dementia, any disorder characterized by abnormal accumulation of α

-synuclein, disorders of the aging process, stroke, bacterial infection, viral infection, Mitochondrial related disease, mental retardation, deafness, blindness, diabetes, obesity, cardiovascular disease, multiple sclerosis, Sjogrens syndrome, lupus, glaucoma, including pseudoexfoliation glaucoma, Leber'"'"'s Hereditary Optic Neuropathy, and rheumatoid arthritis.

20. The method of claim 19, wherein the bacterial infection is Mycobacterium infection.

21. The method of claim 19, wherein the viral infection is Hepatitis C infection.

22. The method of claim 19, wherein the Mitochondrial related disease is selected from one or more of the group consisting of Alpers Disease, Barth Syndrome/LIC (Lethal Infantile Cardiomyopathy), Beta-oxidation Defects, Carnitine-Acyl-Carnitine Deficiency, Carnitine Deficiency, Creatine Deficiency Syndromes, Co-Enzyme Q10 Deficiency, Complex I Deficiency, Complex II Deficiency, Complex III Deficiency, Complex IV Deficiency/COX Deficiency, Complex V Deficiency, CPEO, CPT I Deficiency, CPT II Deficiency, KSS, Lactic Acidosis, LBSL—

Leukodystrohpy, LCAD, LCHAD, Leigh Disease or Syndrome, Luft Disease, MAD/Glutaric Aciduria Type II, MCAD, MELAS, MERRF, MIRAS, Mitochondrial Cytopathy, Mitochondrial DNA Depletion, Mitochondrial Encephalopathy, Mitochondrial Myopathy, MNGIE, NARP, Pearson Syndrome, Pyruvate Carboxylase Deficiency, Pyruvate Dehydrogenase Deficiency, POLG Mutations, Respiratory Chain related disease, SCAD, SCHAD, and VLCAD.

26. The method of claim 1, wherein the compound binds or reacts with the thiol group in a cysteine.

27. The method of claim 1, wherein the cysteine is selected from one or more of the group consisting of C59 and C377 of human Parkin ligase.

28. The method of claim 1, wherein the cysteine is C377 of human Parkin ligase.

29. The method of claim 1, wherein the compound is,

30. The method of claim 16, wherein the amino acid residues of at least one zinc finger corresponds to or aligns within one or more amino acids selected from the group consisting of C59 and C377 of human Parkin Ligase.

31. The method of claim 16, wherein the amino acid residues of at least one zinc finger corresponds to or aligns with C377 of human Parkin Ligase.

32. The method of claim 17, wherein the compound substantially disrupts the structure of at least one zinc finger located in the IBR domain (amino acids 328-377).

23. A pharmaceutical composition for activating a Parkin ligase in a subject, comprising an effective amount of a compound or its salt thereof that disrupts at least one Parkin ligase zinc finger, and a pharmaceutically acceptable carrier;

wherein the compound or its salt thereof can coordinate a zinc ion, and/or bind or react with a cysteine.

24. The pharmaceutical composition of claim 23, wherein the pharmaceutical composition is in a formulation selected from the group consisting of a solid, powder, liquid and a gel.

25. The pharmaceutical composition of claim 23, wherein the compound is selected from the group consisting of compounds of Table 1, Table 2, AH001 and/or AH007.

33. A method of activating a Parkin ligase, comprising administering a compound to a subject in need thereof that acts synergistically with Phospho Ubiquitin (pUB) in activating the Parkin ligase.

34. The method of claim 33, wherein a therapeutically effective amount of the compound disrupts at least one Parkin ligase zinc finger, wherein the compound can coordinate with a zinc ion, and/or bind or react with a cysteine.

35. The method of claim 33, wherein the compound substantially disrupts the structure of at least one zinc finger in the Parkin ligase.

36. The method of claim 35, wherein the amino acid residues of at least one zinc finger corresponds to or aligns within one or more domains selected from the group consisting R0 amino acids 141-216, IBR amino acids 328-377, and R2 amino acids 415-465 of human Parkin Ligase.

37. The method of claim 36, wherein the compound substantially disrupts the structure of at least one zinc finger located in the IBR domain (amino acids 328-377).