Hsp90 activator Aha1 drives production of pathological tau aggregates

Patent metadata

Field	Value
Publication number	US-11318155-B2
Application number	US-201816486975-A
Country	US
Kind code	B2
Filing date	Feb 23, 2018
Priority date	Feb 24, 2017
Publication date	May 3, 2022
Grant date	May 3, 2022

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

The invention claimed is:

1. A method of treating a tauopathy in a subject, the method comprising administering to the subject an ATPase homolog 1 (Aha1) inhibitor, wherein Aha1 inhibitor administration reduces tau accumulation, reduces tau aggregation, reduces interaction between Aha1 and 90 kDa heat shock protein (Hsp90), inhibits Aha1 binding to Hsp90, inhibits an activity of Hsp90, inhibits an ATPase activity of Hsp90, or any combination thereof, and wherein the Aha1 inhibitor comprises 3-(3′,6-dimethoxy-[1,1′-biphenyl]-3-carboxamido)-8-methoxy-2-oxo-2H-chromen-7-yl acetate (KU-177).

2. The method of claim 1 , wherein the Aha1 inhibitor further comprises at least one of N-(7-(((2S,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-8-methoxy-2-oxo-2H-chromen-3-yl)-3′,6-dimethoxy-[1,1′-biphenyl]-3-carboxamide (KU-174), N-(7-hydroxy-8-methoxy-2-oxo-2H-chromen-3-yl)-3′,6-dimethoxy-[1,1′-biphenyl]-3-carboxamide (KU-308), or any combination thereof.

3. The method of claim 2 , wherein the Aha1 inhibitor comprises KU-174.

4. The method of claim 2 , wherein the Aha1 inhibitor comprises KU-308.

5. The method of claim 1 , wherein the subject is diagnosed with 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.

6. The method of claim 5 , wherein subject is diagnosed with Alzheimer's disease.

7. A method of reducing tau aggregation in a subject, the method comprising administering to the subject an Aha1 inhibitor, wherein the Aha1 inhibitor is KU-177.

8. The method of claim 7 , wherein the Aha1 inhibitor further comprises at least one of KU-174, KU-308, or any combination thereof.

9. The method of claim 8 , wherein the Aha1 inhibitor is KU-174.

10. The method of claim 8 , wherein the Aha1 inhibitor is KU-308.

11. The method of claim 7 , wherein the subject is diagnosed with 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.

12. The method of claim 7 , wherein the subject is diagnosed with Alzheimer's disease.

Assignees

• Univ South Florida
• Univ Kansas

Inventors

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

Classifications

• 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

• 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