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.
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