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.

中文翻译：

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发现亨廷顿蛋白-钙调蛋白-蛋白质相互作用的含磺内酰胺小分子干扰剂


亨廷顿病患者中钙调蛋白和突变亨廷顿蛋白之间的异常蛋白质-蛋白质相互作用已被发现有助于亨廷顿病的进展。对能够破坏这种相互作用的小分子的高通量筛选揭示了磺内酰胺系列作为有效的小分子破坏剂。磺内酰胺支架的多样化提供了一组 24 个类似物或进一步评估。发现了类似物组中的几种结构-活性趋势，最显着的是绝对立体化学的影响可以忽略不计，以及与吸电子芳香族取代基的强有益相关性。最有希望的类似物对相关激酶的脱靶效应进行了分析，最终，评估了一种候选分子在亨廷顿病神经元细胞模型中的神经保护作用。