Compositions and methods for treating alzheimer's disease and other tauopathies
View Patent ↗Compounds, pharmaceutical compositions, and methods of using such compounds and compositions to treat or prevent Alzheimer's disease and related tauopathies through the inhibition of USP-9X and/or enhancement of SCF(β-TrCP).
1. A composition for treating Alzheimer's disease, the composition comprising a USP-9x inhibitor having the structure:
2. The composition of claim 1 , further comprising a pharmaceutically acceptable carrier.
3. The composition of claim 1 , wherein the USP-9x inhibitor is present in a therapeutically effective amount.
4. The composition of claim 1 , wherein the USP-9x inhibitor is present in a prophylactically effective amount.
5. The composition of claim 1 , wherein the SCF(β-TrCP) enhancer is present in a therapeutically effective amount.
6. The composition of claim 1 , wherein the SCF(β-TrCP) enhancer is present in a prophylactically effective amount.
7. The composition of claim 1 , wherein the SCF(β-TrCP) enhancer is a gene therapy.
8. The composition of claim 1 , wherein the SCF(β-TrCP) enhancer increases the neddylation of Cullin.
9. The composition of claim 8 , wherein the SCF(β-TrCP) enhancer increases the expression or activity of NEDD8 or NAE.
10. The composition of claim 8 , wherein the SCFM(β-TrCP) enhancer is a gene therapy that increases expression of NEDD8 or NAE.
11. The composition of claim 8 , wherein the SCFM(β-TrCP) enhancer is a small molecule activator of NAE.
12. The composition of claim 8 , wherein the SCFM(β-TrCP) enhancer increases activity and/or expression of CAND1.
13. The composition of claim 8 , wherein the SCFM(β-TrCP) enhancer increases expression of CAND1 by a gene therapy.
14. The composition of claim 8 , wherein the SCFM(β-TrCP) enhancer increases activity of CAND1 through administration of a small molecule activator of CAND1.
15. The composition of claim 8 , wherein the SCFM(β-TrCP) enhancer decreases Cullin deneddylation.
16. The composition of claim 15 , wherein the SCFM(β-TrCP) enhancer inhibits CSN.
17. The composition of claim 15 , wherein the SCFM(β-TrCP) enhancer is RNAi targeting CSN.
18. The composition of claim 17 , wherein the RNAi is miRNA targeting CSN.
19. The composition of claim 17 , wherein the RNAi is sRNA targeting CSN.
20. The composition of claim 17 , wherein, the RNAi is shRNA targeting CSN.
21. The composition of claim 17 , wherein the SCFM(β-TrCP) enhancer is a small molecule inhibitor of CSN.
22. A kit comprising a USP-9x inhibitor having the structure:
a SCFM(β-TrCP) enhancer; and
a pharmaceutically acceptable carrier thereof.
23. The kit of claim 22 , wherein the inhibitor and the enhancer are coformulated.
24. The kit of claim 22 , wherein the inhibitor and the enhancer are copackaged.
25. The kit of claim 22 , further comprising instructions for treatment of Alzheimer's disease.
26. The composition of claim 1 , wherein the composition is effective in treating tauopathies selected from the group consisting of: Creutzfeldt-Jakob disease, dementia pugilistica, Down's syndrome, Gerstmann-Straussler-Sheinker disease, inclusion-body myositis, frontotemporal dementia (FTD), Pick's disease, tangle-predominant Alzheimer's disease, corticobasal degeneration, amyotrophic lateral sclerosis/parkinsonism-dementia complex, argyrophilic grain dementia, diffuse neurofibrillary tangles with calcification, Hallevorden-Spatz disease, multiple system atrophy, Niemann-Pick disease, Type C1 progressive subcortial gliosis, progressive supranuclear palsy and subacute sclerosing panencephalitis.