Histone acetyltransferase activators and uses thereof

Abstract

The invention provides for a method for screening compounds that bind to and modulate a histone acetyltransferase protein. The invention further provides methods for treating neurodegenerative disorders, conditions associated with accumulated amyloid-beta peptide deposits, Tau protein levels, and/or accumulations of alpha-synuclein as well as cancer by administering a HAT-activating compound to a subject.

1 . A method for treating a neurodegenerative disease in a subject, the method comprising administering to a subject a therapeutic amount of a pharmaceutical composition comprising a compound having the following structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof. 
       
     
     
         2 . The method of  claim 1 , wherein the neurodegenerative disease comprises Adrenoleukodystrophy (ALD), Alcoholism, Alexander's disease, Alper's disease, Alzheimer's disease, Amyotrophic lateral sclerosis (Lou Gehrig's Disease), Ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjögren-Batten disease), Bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt-Jakob disease, Familial fatal insomnia, Frontotemporal lobar degeneration, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe's disease, Lewy body dementia, Neuroborreliosis, Machado-Joseph disease (Spinocerebellar ataxia type 3), Multiple System Atrophy, Multiple sclerosis, Narcolepsy, Niemann Pick disease, Parkinson's disease, Pelizaeus-Merzbacher Disease, Pick's disease, Primary lateral sclerosis, Prion diseases, Progressive Supranuclear Palsy, Rett's syndrome, Tau-positive FrontoTemporal dementia, Tau-negative FrontoTemporal dementia, Refsum's disease, Sandhoff disease, Schilder's disease, Subacute combined degeneration of spinal cord secondary to Pernicious Anaemia, Spielmeyer-Vogt-Sjogren-Batten disease, Batten disease, Spinocerebellar ataxia, Spinal muscular atrophy, Steele-Richardson-Olszewski disease, Tabes dorsalis, or Toxic encephalopathy. 
     
     
         3 . The method of  claim 2 , wherein the neurodegenerative disease comprises Alzheimer's disease, Huntington's disease, or Parkinson's disease. 
     
     
         4 . The method of  claim 1 , wherein the compound is a pharmaceutically acceptable salt thereof. 
     
     
         5 . The method of  claim 1 , wherein the compound is an acid addition salt thereof. 
     
     
         6 . The method of  claim 1 , wherein the compound is a hydrochloride salt thereof. 
     
     
         7 . The method of  claim 1 , wherein the effective amount is at least about 1 mg/kg body weight, at least about 2 mg/kg body weight, at least about 3 mg/kg body weight, at least about 4 mg/kg body weight, at least about 5 mg/kg body weight, at least about 6 mg/kg body weight, at least about 7 mg/kg body weight, at least about 8 mg/kg body weight, at least about 9 mg/kg body weight, at least about 10 mg/kg body weight, at least about 15 mg/kg body weight, at least about 20 mg/kg body weight, at least about 25 mg/kg body weight, at least about 30 mg/kg body weight, at least about 40 mg/kg body weight, at least about 50 mg/kg body weight, at least about 75 mg/kg body weight, or at least about 100 mg/kg body weight. 
     
     
         8 . A method for increasing memory retention in a subject afflicted with a neurodegenerative disease, the method comprising administering to a subject a therapeutic amount of a pharmaceutical composition comprising a compound having the following structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof. 
       
     
     
         9 . The method of  claim 8 , wherein the neurodegenerative disease comprises Alzheimer's disease, Huntington's disease, or Parkinson's disease. 
     
     
         10 . The method of  claim 8 , wherein the compound is a pharmaceutically acceptable salt thereof. 
     
     
         11 . The method of  claim 8 , wherein the compound is an acid addition salt thereof. 
     
     
         12 . The method of  claim 8 , wherein the compound is a hydrochloride salt thereof. 
     
     
         13 . A method for increasing synaptic plasticity in a subject afflicted with a neurodegenerative disease, the method comprising administering to a subject a therapeutic amount of a composition that increases histone acetylation in the subject, wherein the composition comprises a compound having the following structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof. 
       
     
     
         14 . The method of  claim 13 , wherein synaptic plasticity comprises learning, memory, or a combination thereof. 
     
     
         15 . The method of  claim 13 , wherein synaptic plasticity comprises long term potentiation (LTP). 
     
     
         16 . The method of  claim 13 , wherein the neurodegenerative disease comprises Alzheimer's disease, Huntington's disease, or Parkinson's disease. 
     
     
         17 . The method of  claim 13 , wherein the compound is a pharmaceutically acceptable salt thereof. 
     
     
         18 . The method of  claim 13 , wherein the compound is an acid addition salt thereof. 
     
     
         19 . The method of  claim 13 , wherein the compound is a hydrochloride salt thereof.