Methods for selecting phosphatase selective and non-selective phosphatase inhibitors

Abstract

The present invention discloses a method to discover selective inhibitors of phosphatases. Thus, the invention provides a method for screening a test compound to determine whether the compound binds a holophosphatase selectively or non-selectively comprising: i) providing a first holophosphatase wherein said holophosphatase is captured/immobilised; ii) testing a test compound for its ability to bind to the first holophosphatase; iii) providing a second holophosphatase wherein said second holophosphatase is captured/immobilised; iv) testing the same test compound for its ability to bind to the second holophosphatase; v) comparing the binding of the test compound to said first holophosphatase with the binding to said second phosphatase wherein a compound that binds a holophosphatase selectively will bind to said first holophosphatase but not said second holophosphatase; or will bind to said second holophosphatase but not said first; or wherein a compound that binds a holophosphatase non-selectively will bind to both said first holophosphatase and said second holophosphatase.

1 - 27 . (canceled) 
     
     
         28 . A method of treating a subject having a disorder associated with accumulation of misfolded proteins, a proteostasis disorder, a myelin disorder, or a metabolic disorder, wherein the method comprises administering to the subject a therapeutically effective amount of a PPP1R115B selective inhibitor, wherein the PPP1R15B selective inhibitor is (E)-2-(2,3-dichlorobenzylidene)hydrazine-1-carboximidamide or a salt thereof. 
     
     
         29 . The method of  claim 28 , wherein the disorder is a myelin disorder and is selected from multiple sclerosis, Pelizaeus-Merzbacher disease, vanishing white matter disease, acute disseminated encephalomyelitis, periventricular leukomalacia, periventricular white matter injury, Tabes Dorsalis, Devic's disease, optic neuritis, progressive multifocal leukoencephalopathy, transverse myelitis, chronic inflammatory demyelinating polyneuropathy, anti-MAG peripheral neuropathy, adrenoleukodystrophy, adrenomyeloneuropathy, diffuse white matter injury, Guillain-Barre Syndrome, central pontine myelinolysis, or an inherited demyelinating disease. 
     
     
         30 . The method of  claim 29 , wherein the disorder is an inherited demyelinating disease selected from leukodystrophy or Charcot Marie Tooth disease. 
     
     
         31 . The method of  claim 28 , wherein the disorder is a metabolic disorder and is selected from diabetes, Wolcott-Rallison syndrome, obesity, insulin resistance, hyperlipidemia, fatty liver disease, or atherosclerosis. 
     
     
         32 . The method of  claim 28 , wherein the disorder is selected from retinal degeneration, glaucoma, amyotrophic lateral sclerosis, a tauopathy, or a prion disease. 
     
     
         33 . The method of  claim 28 , wherein the disorder is associated with aggregation of the microtubule-associated protein tau. 
     
     
         34 . The method of  claim 33 , wherein the disorder associated with aggregation of the microtubule-associated protein tau is selected from Alzheimer's disease, amyotrophic lateral sclerosis, parkinsonism, dementia, argyrophilic grain disease, chronic traumatic encephalopathy, corticobasal degeneration, diffuse neurofibrillary tangles with calcification, Down's syndrome, familial British dementia, familial Danish dementia, frontotemporal dementia and parkinsonism linked to chromosome 17, frontotemporal lobar degeneration, Gerstmann-Sträussler-Scheinker disease, Gaudeloupean parkinsonism, myotonic dystrophy, neurodegeneration with brain iron accumulation, Niemann-Pick disease type C, non-Guamanian motor neuron disease with neurofibrillary tangles, Pick's disease, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear palsy, SLC9A6-related mental retardation, subacute sclerosing panencephalitis, tangle-only dementia, or white matter tauopathy with globular glial inclusions. 
     
     
         35 . The method of  claim 28 , wherein the disorder is a disease caused by misfolding or trafficking defects of a protein made in the endoplasmic reticulum. 
     
     
         36 . The method of  claim 35 , wherein the disease is selected from cystic fibrosis caused by mutations impairing folding of the transmembrane protein, congenital hypothyroid goiter with thyroglobulin deficiency due to the misfolding and/or trafficking defect of the hormone thyroglobulin, familial neurohypophyseal diabetes insipidus caused by misfolding and absence of circulating arginine vasopressin, procollagen biosynthesis disorders where the disease is caused by a failure to fold, assemble and synthesize collagen, a genetic disease of connective tissues, hypercholesterolemia, Alpha-1 antitrypsin deficiencies due to the misfolding of alpha 1 antitrypsin, lysosomal disorder due to misfolding of proteins associated for lysosomal function, retinitis pigmentosa which is caused by the misfolding of rhodopsin proteins, or inflammatory bowel disease. 
     
     
         37 . The method of  claim 36 , wherein the disease is osteogenesis imperfect. 
     
     
         38 . The method of  claim 36 , wherein the disease is growth plate dysplasia associated with defects of proteins from extracellular matrix. 
     
     
         39 . The method of  claim 36 , wherein the disease is hypercholesterolemia with molecular defects caused by mutations in the LDL receptor causing lack of synthesis, altered intracellular transport, or abnormal function. 
     
     
         40 . The method of  claim 36 , wherein the disease is Gaucher disease, Niemann-Pick disease, or Anderson-Fabry disease.