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Inhibition of the MSUT2: RNA interaction for the treatment of tauopathies
Author(s) -
Baker Jeremy D,
Kraemer Brian C
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.047632
Subject(s) - tauopathy , drug discovery , repurposing , drug repositioning , computational biology , neurodegeneration , drug , virtual screening , chemistry , pharmacology , biology , biochemistry , medicine , ecology , disease
Background Our previous work revealed RNA binding protein MSUT2 drives tau‐mediated neurodegeneration and cognitive decline in mouse models of tauopathy. Therefore, we hypothesized that MSUT2 inhibitors could be therapeutic for tauopathy disorders. Here we have designed a drug‐discovery workflow for the identification of MSUT2 inhibitors to be used as tool compounds, potential therapeutic compounds, and to be used for probing the underlying MSUT2 mechanism of pathology. Method We employed a drug repurposing screening strategy for the identification of MSUT2 modifying compounds. We developed both fluorescent polarization and alpha assay screens for small molecule discovery from a well validated drug repurposing library. Our workflow included validation of hits by dose response analysis, specificity testing against MSUT2 binding partner PABPN1, orthogonal assays of activity, as well as testing for cytotoxicity. Result Screening of a 700 compound drug repurposing library against MSUT2 activity resulted in a 1.7% hit rate for significant MSUT2 inhibitors. Subsequent validation studies presented narrowed these hits to 3 potential tool compounds with dose responsive activity and selectivity against MSUT2 with relatively low cytotoxic characteristics. Conclusion Work here serves as proof of principle strategy for finding inhibitors of the RNA‐binding protein MSUT2 for the treatment of tauopathies.