METHODS FOR MODULATING SET AND USES THEREOF

• US 20100144627A1
• Filed: 12/21/2007
• Published: 06/10/2010
• Est. Priority Date: 12/21/2006
• Status: Active Grant

• Current Assignee: Cornerstone Biosciences, Inc.
• Original Assignee: Cognosci, Inc.
• Inventors: Oddo, Jessica, Vitek, Michael P., Christensen, Dale J.
• Granted Patent: US 9,730,979 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• CPC Class Codes: A61K 38/1709 from mammals
• 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 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• 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 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• 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: 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 14/775 : Apolipopeptides

Abstract

The present invention provides methods for modulating SET activity by contacting SET with a binding agent such as an ApoE peptide derivative. In one embodiment of the invention, a pharmaceutical composition capable of modulating SET activity is administered to a patient for the treatment of an inflammatory or neurological condition. In another embodiment of the invention, compounds efficacious for the treatment of inflammatory and neurological conditions are identified by screening for a binding agent capable of competing with or inhibiting the binding of an ApoE derivative to SET.

Claims

1. A method of modulating an activity of SET comprising contacting SET with an exogenous agent capable of binding SET.

2. The method of claim 1, wherein the agent increases said SET activity.

3. The method of claim 1, wherein the agent decreases said SET activity.

4. The method of claim 1, wherein the agent is a peptide.

5. The method of claim 1, wherein the agent is an ApoE analog.

6. The method of claim 5, wherein the agent is a peptide containing the sequence of SEQ ID NO:

1.

7. The method of claim 6, wherein said peptide contains SEQ ID NO:

1 linked to one to five additional amino acids or amino acid analogs at the N-terminus or C-terminus or both the N-terminus and C-terminus, wherein such additional amino acids do not adversely affect the ability of the peptide to modulate SET activity.

8. The method of claim 6, wherein said peptide contains 18 amino acids or more.

9. The method of claim 6, wherein said peptide contains 20 amino acids or more.

10. The method of claim 6, wherein said peptide contains 30 amino acids or more.

11. The method of claim 6, wherein said peptide contains 40 amino acids or more.

12. The method of claim 6, wherein said peptide consists essentially of SEQ ID NO:

1.

13. The method of claim 6, wherein said peptide consists of SEQ ID NO:

1.

14. The method of claim 5, wherein the agent is a peptide containing the sequence of SEQ ID NO:

2.

15. The method of claim 14, wherein said peptide contains SEQ ID NO:

2 linked to one to five additional amino acids or amino acid analogs at the N-terminus or C-terminus or both the N-terminus and C-terminus, wherein such additional amino acids do not adversely affect the ability of the peptide to modulate SET activity.

16. The method of claim 14, wherein said peptide contains 13 amino acids or more.

17. The method of claim 14, wherein said peptide contains 18 amino acids or more.

18. The method of claim 14, wherein said peptide contains 20 amino acids or more.

19. The method of claim 14, wherein said peptide contains 30 amino acids or more.

20. The method of claim 14, wherein said peptide contains 40 amino acids or more.

21. The method of claim 14, wherein said peptide consists essentially of SEQ ID NO:

2.

22. The method of claim 14, wherein said peptide consists of SEQ ID NO:

2.

23. The method of claim of claim 1, wherein the agent competes with a peptide containing the sequence of SEQ ID NO:

1 for binding to SET.

24. The method of claim 23, wherein the agent inhibits binding of the peptide to SET.

25. The method of claim 1, wherein administration of the agent reduces phosphorylated p38 MAP kinase.

26. The method of claim 1, wherein administration of the agent reduces LPS-induced nitric oxide.

27. The method of claim 1, wherein administration of the agent decreases phosphatase activity of PP2A.

28. The method of claim 1, wherein administration of the agent increases phosphatase activity of PP2A.

29. The method of claim 1, wherein administration of the agent reduces Jcasp-induced cell death.

30. The method of claim 1, wherein administration of the agent reduces kinase activity of cdk5.

31. The method of claim 1, wherein an effective amount of the said agent is administered to a subject suffering from an inflammatory or neurological condition.

32. The method of claim 31, wherein the inflammatory condition affects the nervous system.

33. The method of claim 32, wherein the inflammatory condition is multiple sclerosis, vasculitis, acute disseminated encephalomyelitis, Guillain-Barre syndrome or sepsis.

34. The method of claim 31, wherein the neurological condition is an acute CNS injury.

35. The method of claim 34, wherein the acute CNS injury is traumatic brain injury, stroke, closed head injury, global cerebral ischemia, cerebral edema, focal ischemia, subarachnoid hemorrhage, or intracranial hemorrhage.

36. The method of claim 31, wherein the neurological condition is a chronic neurological disease.

37. The method of claim 36, wherein the chronic neurological disease is Alzheimer'"'"'s disease, a disease associated with tauopathy, HIV-associated encephalopathy, neurolathyrism, amyotrophic lateral sclerosis (ALS), Huntington'"'"'s chorea, Parkinson'"'"'s disease, epilepsy, d-2-hydroxyglutaric aciduria or schizophrenia.

38. The method of claim 37, wherein the disease associated with tauopathy is selected from the group consisting of progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick'"'"'s disease (PiD), and argyrophilic grain disease (AGD).

39. The method of claim 38, wherein administration of an effective amount of said agent reduces phosphorylation of tau protein in neurons of said subject.

40. The method of claim 31, wherein the neurological condition increases microglial activation, glial activation or neuronal cell death.

41. The method of claim 31, wherein administration of the agent reduces glial activation, microglial activation or neuronal cell death.

42. The method of claim 31, wherein said inflammatory condition is an autoimmune disease.

43. The method of claim 42, wherein said autoimmune disease is selected from the group consisting of rheumatoid arthritis, colitis, psoriasis, lupus, and diabetes (type 1).

44. The method of claim 1, wherein an effective amount of the said agent is administered to a subject suffering from cancer.

45. The method of claim 44, wherein the cancer is leukemia.

46. The method of claim 1, wherein an effective amount of the said agent is administered to a subject suffering from myelodysplastic syndrome.

47. The method of claim 1, wherein an effective amount of the said agent is administered to a subject suffering from tuberous sclerosis.

48. The method of claim 1, wherein SET has the sequence of SEQ ID NO:

3 or SEQ ID NO;

4.

49. A method of identifying an agent that binds to SET and modulates SET activity, comprising

contacting SET with at least one test agent to identify one or more agents that bind to SET, and

screening said one or more agents for the ability to compete with or inhibit binding of a peptide containing SEQ ID NO:

1 to SET.

50. The method of claim 49, further comprising

isolating one or more agents that compete with or inhibit binding of a peptide containing SEQ ID NO:

1 to SET.

51. The method of claim 50, further comprising

screening said one or more agents for the ability to increase phosphatase activity of PP2A.

52. The method of claim 50, further comprising

screening said one or more agents for the ability to decrease kinase activity of cdk5.

53. A medicament comprising said isolated one or more agents of claim 50 and a pharmaceutically acceptable carrier.

54. A method of increasing the pool of active PP2A in a cell comprising

administering an agent to said cell wherein said agent binds to SET preventing SET from binding to PP2A.

55. The method of claim 54, wherein said agent is a peptide.

56. The method of claim 55, wherein said peptide contains the sequence of SEQ ID NO:

1.

57. The method of claim 55, wherein said peptide contains the sequence of SEQ ID NO:

2.

58. The method of claim 54, wherein said agent is an ApoE analog.