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Discovery of sultam-containing small-molecule disruptors of the huntingtin–calmodulin protein–protein interaction
Klus, Nicholas J. Kapadia, Khushboo McDonald, Peter Roy, Anuradha Frankowski, Kevin J. Muma, Nancy A. Aubé, Jeffrey
Klus, Nicholas J.
Kapadia, Khushboo
McDonald, Peter
Roy, Anuradha
Frankowski, Kevin J.
Muma, Nancy A.
Aubé, Jeffrey
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Abstract
The aberrant protein–protein interaction between calmodulin and mutant huntingtin protein in Huntington’s disease patients has been found to contribute to Huntington’s disease progression. A high-throughput screen for small molecules capable of disrupting this interaction revealed a sultam series as potent small-molecule disruptors. Diversification of the sultam scaffold afforded a set of 24 analogs or further evaluation. Several structure–activity trends within the analog set were found, most notably a negligible effect of absolute stereochemistry and a strong beneficial correlation with electron-withdrawing aromatic substituents. The most promising analogs were profiled for off-target effects at relevant kinases and, ultimately, one candidate molecule was evaluated for neuroprotection in a neuronal cell model of Huntington’s disease.
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2020-06-12
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Springer
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Klus_2020.pdf
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Huntington’s disease, High-throughput screening, Neurodegeneration, Structure–activity relationship studies
Citation
Klus, N.J., Kapadia, K., McDonald, P. et al. Discovery of sultam-containing small-molecule disruptors of the huntingtin–calmodulin protein–protein interaction. Med Chem Res 29, 1187–1198 (2020). https://doi.org/10.1007/s00044-020-02583-8