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Discovery of sultam-containing small-molecule disruptors of the huntingtin-calmodulin protein-protein interaction.

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.

SUBMITTER: Klus NJ 

PROVIDER: S-EPMC7906539 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Discovery of sultam-containing small-molecule disruptors of the huntingtin-calmodulin protein-protein interaction.

Klus Nicholas J NJ   Kapadia Khushboo K   McDonald Peter P   Roy Anuradha A   Frankowski Kevin J KJ   Muma Nancy A NA   Aubé Jeffrey J  

Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents 20200612 7

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 n  ...[more]

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