The hsp90 activator aha1 drives production of pathological tau aggregates

Patent metadata

Field	Value
Publication number	US-2021128597-A1
Application number	US-201816486975-A
Country	US
Kind code	A1
Filing date	Feb 23, 2018
Priority date	Feb 24, 2017
Publication date	May 6, 2021
Grant date	—

Abstract

Disclosed herein are compounds and methods for inhibiting Aha1 for the treatment of tauopathies and neurodegenerative diseases. The Aha1 inhibitor may reduce the interaction between Aha1 and Hsp90. The Aha1 inhibitor may reduce aggregation of tau protein. The Aha1 inhibitor may include a compound selected from KU-177, KU-174, and KU-308.

First claim

1 .- 20 . (canceled)

21 . A method of treating a tauopathy in a subject, the method comprising administering to the subject an Aha1 inhibitor, wherein Aha1 inhibitor administration reduces tau accumulation, reduces tau aggregation, reduces interaction between Aha1 and Hsp90, inhibits Aha1 binding to Hsp90, inhibits the activity of Hsp90, inhibits the ATPase activity Hsp90, or any combination thereof.

22 . The method of claim 21 , wherein the Aha1 inhibitor comprises at least one of KU-177, KU-174, KU-308, or any combination thereof.

23 . The method of claim 22 , wherein the Aha1 inhibitor comprises KU-177.

24 . The method of claim 22 , wherein the Aha1 inhibitor comprises KU-174.

25 . The method of claim 22 , wherein the Aha1 inhibitor comprises KU-308.

26 . The method of claim 21 , wherein the tauopathy comprises at least one of neurodegenerative disease, Alzheimer's disease (AD), neuronal loss, cognitive defect, primary age-related tauopathy, chronic traumatic encephalopathy, progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia and parkinsonism linked to chromosome 17, Lytico-Bodig disease, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, and lipofuscinosis.

27 . The method of claim 26 , wherein the tauopathy comprises Alzheimer's disease.

28 . A method of reducing tau aggregation in a subject, the method comprising administering to the subject an Aha1 inhibitor.

29 . The method of claim 28 , wherein the Aha1 inhibitor comprises at least one of KU-177, KU-174, KU-308, or any combination thereof.

30 . The method of claim 29 , wherein the Aha1 inhibitor is KU-177.

31 . The method of claim 29 , wherein the Aha1 inhibitor is KU-174.

32 . The method of claim 29 , wherein the Aha1 inhibitor is KU-308.

33 . The method of claim 28 , wherein the tauopathy comprises at least one of neurodegenerative disease, Alzheimer's disease (AD), neuronal loss, cognitive defect, primary age-related tauopathy, chronic traumatic encephalopathy, progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia and parkinsonism linked to chromosome 17, Lytico-Bodig disease, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, and lipofuscinosis.

34 . The method of claim 28 , wherein the tauopathy comprises Alzheimer's disease.

35 . A composition comprising an Aha1 inhibitor, wherein the Aha1 inhibitor comprises at least one of KU-177, KU-174, KU-308, or any combination thereof, for the treatment of a tauopathy in a subject.

36 . The composition of claim 35 , further comprising a pharmaceutically acceptable carrier.

37 . The composition of claim 35 , wherein the Aha1 inhibitor comprises a therapeutically effective amount, wherein the therapeutically effective amount is between approximately 1 mg/kg and 1000 mg/kg.

Assignees

• Univ South Florida
• Univ Kansas

Inventors

• Dickey Chad
• Shelton Lindsey
• Blagg Brian
• Koren John
• Blair Laura

Classifications

• A61K31/7048 Primary

  having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin} · CPC title

• A61K31/366

  having six-membered rings, e.g. delta-lactones · CPC title

• A61P25/28 Primary

  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 title