DAPH analogs and inhibition of protein aggregation

A method for disaggregating protein oligomers and/or protein fibers, comprising,

• contacting protein fibers with DAPH or one or more DAPH analogs, salts thereof and solvates thereof, in an amount effective to disaggregate the protein oligomers or the protein fibers,
• optionally wherein the disaggregation reduces toxicity of the protein oligomers and/or protein fibers,
• optionally wherein 4,5-dianilinophthalimide (DAPH), a salt thereof or a solvate thereof is used,
• optionally wherein the DAPH analog is 5,6-Bis-(4-fluoro-phenylamino)-isoindole-1,3-dione (DAPH-7), 5,6-Bis-(4-methoxy-phenylamino)-isoindole-1,3-dione (DAPH-12), bisindolylmaleimide IV (DAPH-13), a salt thereof or a solvate thereof,
• optionally wherein the protein is selected from the group consisting of amyloid β (Aβ), huntingtin, PrP prion, α-synuclein, cytoplasmic polyadenylation element binding protein (CPEB), yeast Sup35 NM protein (PSI+ prion), synphilin, transthyretin, tau, ataxin 1, ataxin 3, atrophin, cystatin B, cystic fibrosis transmembrane conductance regulator (CFTR), the variable domain of immunoglobulin light chains, insulin, leptin, α-lactalbumin, phosphodiesterase γ, prothymosin α and apo-lipoprotein E4, and androgen receptor, and/or
• optionally wherein the protein fibers are amyloid fibrils.

A method for inhibiting aggregation of protein oligomers and/or protein fibers, comprising,

• contacting protein oligomers and/or protein fibers with DAPH or one or more DAPH analogs, salts thereof and solvates thereof, in an amount effective to disaggregate the protein oligomers or the protein fibers,
• optionally wherein the inhibition of aggregation reduces toxicity of the protein oligomers and/or protein fibers,
• optionally wherein 4,5-dianilinophthalimide (DAPH), a salt thereof or a solvate thereof is used,
• optionally wherein the DAPH analog is 5,6-Bis-(4-fluoro-phenylamino)-isoindole-1,3-dione (DAPH-7), 5,6-Bis-(4-methoxy-phenylamino)-isoindole-1,3-dione (DAPH-12), or bisindolylmaleimide IV (DAPH-13), or a salt thereof or a solvate thereof,
• optionally wherein the protein is selected from the group consisting of amyloid γ (Aγ), huntingtin, PrP prion, α-synuclein, cytoplasmic polyadenylation element binding protein (CPEB), yeast Sup35 NM protein (PSI+ prion), synphilin, transthyretin, tau, ataxin 1, ataxin 3, atrophin, cystatin B, cystic fibrosis transmembrane conductance regulator (CFTR), the variable domain of immunoglobulin light chains, insulin, leptin, α-lactalbumin, phosphodiesterase γ, prothymosin α and apo-lipoprotein E4, and androgen receptor, and/or
• optionally wherein the protein fibers are amyloid fibrils.

A method for disaggregating or inhibiting aggregation of protein oligomers and/or protein fibers, comprising

• contacting protein oligomers and/or protein fibers with (a) 4,5-dianilinophthalimide (DAPH), salts thereof or solvates thereof and (b) one or more DAPH analogs, salts thereof or solvates thereof, in a combined amount effective to disaggregate and/or inhibit aggregation of the protein oligomers or the protein fibers,
• optionally wherein the disaggregation and/or inhibition of aggregation reduces toxicity of the protein oligomers and/or protein fibers, optionally wherein the DAPH analog is 5,6-Bis-(4-fluoro-phenylamino)-isoindole-1,3-dione (DAPH-7), 5,6-Bis-(4-methoxy-phenylamino)-isoindole-1,3-dione (DAPH-12), bisindolylmaleimide IV (DAPH-13), or a salt thereof or a solvate thereof,
• optionally wherein the protein is selected from the group consisting of amyloid β (Aβ), huntingtin, PrP prion, α-synuclein, cytoplasmic polyadenylation element binding protein (CPEB), yeast Sup35 NM protein (PSI+ prion), synphilin, transthyretin, tau, ataxin 1, ataxin 3, atrophin, cystatin B, cystic fibrosis transmembrane conductance regulator (CFTR), the variable domain of immunoglobulin light chains, insulin, leptin, α-lactalbumin, phosphodiesterase γ, prothymosin α and apo-lipoprotein E4, and androgen receptor, and/or
• optionally wherein the protein fibers are amyloid fibrils.

A method for treating a subject having a protein aggregation disorder, comprising

• administering to a subject in need of such treatment DAPH or one or more DAPH analogs, salts thereof and solvates thereof, in an amount effective to disaggregate protein oligomers or protein fibers and/or to inhibit aggregation of protein oligomers and/or protein fibers,
• optionally wherein the disaggregation and/or inhibition of aggregation reduces toxicity of the protein oligomers and/or protein fibers,
• optionally wherein 4,5-dianilinophthalimide (DAPH), a salt thereof or a solvate thereof is administered,
• optionally wherein the DAPH analog is 5,6-Bis-(4-fluoro-phenylamino)-isoindole-1,3-dione (DAPH-7), 5,6-Bis-(4-methoxy-phenylamino)-isoindole-1,3-dione (DAPH-12), or bisindolylmaleimide IV (DAPH-13), or a salt thereof or a solvate thereof,
• optionally wherein the protein is selected from the group consisting of amyloid β (Aβ) huntingtin, PrP prion, α-synuclein, cytoplasmic polyadenylation element binding protein (CPEB), yeast Sup35 NM protein (PSI+ prion), synphilin, transthyretin, tau, ataxin 1, ataxin 3, atrophin, cystatin B, cystic fibrosis transmembrane conductance regulator (CFTR), the variable domain of immunoglobulin light chains, insulin, leptin, α-lactalbumin, phosphodiesterase γ, prothymosin α and apo-lipoprotein E4, and androgen receptor,
• optionally wherein the protein fibers are amyloid fibrils,
• optionally wherein the protein aggregation disorder is selected from the group consisting of Alzheimer's disease;
• tauopathy;
• α-synucleinopathy;
• Parkinson's disease;
• Huntington's Disease;
• prion related diseases;
• Type II Diabetes Mellitus associated with islet amyloid polypeptide (IAPP);
• and neurodegenerative diseases associated with intracellular and/or intraneuronal aggregates of proteins with polyglutamine, polyalanine or other repeats arising from pathological expansions of tri- or tetra-nucleotide elements within corresponding genes, and/or
• optionally wherein the subject is free of symptoms otherwise calling for treatment with the composition.

A method for treating a subject having a protein aggregation disorder, comprising

• administering to a subject in need of such treatment (a) 4,5-dianilinophthalimide (DAPH), salts thereof or solvates thereof and (b) one or more DAPH analogs, salts thereof or solvates thereof, in a combined amount effective to disaggregate or to inhibit aggregation of protein oligomers and/or protein fibers,
• optionally wherein the disaggregation and/or the inhibition of aggregation reduces toxicity of the protein oligomers and/or protein fibers,
• optionally wherein the DAPH analog is 5,6-Bis-(4-fluoro-phenylamino)-isoindole-1,3-dione (DAPH-7), 5,6-Bis-(4-methoxy-phenylamino)-isoindole-1,3-dione (DAPH-12), or bisindolylmaleimide IV (DAPH-13), or a salt thereof or a solvate thereof,
• optionally wherein the protein is selected from the group consisting of amyloid β (Aβ), huntingtin, PrP prion, α-synuclein, cytoplasmic polyadenylation element binding protein (CPEB), yeast Sup35 NM protein (PSI+ prion), synphilin, transthyretin, tau, ataxin 1, ataxin 3, atrophin, cystatin B, cystic fibrosis transmembrane conductance regulator (CFTR), the variable domain of immunoglobulin light chains, insulin, leptin, α-lactalbumin, phosphodiesterase γ, prothymosin α and apo-lipoprotein E4, and androgen receptor,
• optionally wherein the protein fibers are amyloid fibrils,
• optionally wherein the protein aggregation disorder is selected from the group consisting of Alzheimer's disease;
• tauopathy:
• α-synucleinopathy;
• Parkinson's disease:
• Huntington's Disease:
• prion related diseases:
• Type II Diabetes Mellitus associated with islet amyloid polypeptide (IAPP):
• and neurodegenerative diseases associated with intracellular and/or intraneuronal aggregates of proteins with polyglutamine, polyalanine or other repeats arising from pathological expansions of tri- or tetra-nucleotide elements within corresponding genes, and/or
• optionally wherein the subject is free of symptoms otherwise calling for treatment with the composition.

A composition comprising

• 4,5-dianilinophthalimide (DAPH), salts thereof or solvates thereof, and
• one or more DAPH analogs, salts thereof or solvates thereof,
• optionally comprising a pharmaceutically acceptable carrier,
• optionally wherein the compounds are present in a combined amount effective to inhibit aggregation of protein oligomers and/or protein fibers or disaggregate protein oligomers and/or protein fibers,
• optionally wherein the DAPH analog is 5,6-Bis-(4-fluoro-phenylamino)-isoindole-1,3-dione (DAPH-7), 5,6-Bis-(4-methoxy-phenylamino)-isoindole-1,3-dione (DAPH-12), or bisindolylmaleimide IV (DAPH-13), or a salt thereof or a solvate thereof,