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dc.contributor.authorKlus, Nicholas J.
dc.contributor.authorKapadia, Khushboo
dc.contributor.authorMcDonald, Peter
dc.contributor.authorRoy, Anuradha
dc.contributor.authorFrankowski, Kevin J.
dc.contributor.authorMuma, Nancy A.
dc.contributor.authorAubé, Jeffrey
dc.date.accessioned2022-02-01T16:21:24Z
dc.date.available2022-02-01T16:21:24Z
dc.date.issued2020-06-12
dc.identifier.citationKlus, 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/s00044-020-02583-8en_US
dc.identifier.urihttp://hdl.handle.net/1808/32487
dc.description.abstractThe 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.en_US
dc.publisherSpringeren_US
dc.rightsCopyright © 2020, Springer Science Business Media, LLC, part of Springer Nature.en_US
dc.subjectHuntington’s diseaseen_US
dc.subjectHigh-throughput screeningen_US
dc.subjectNeurodegenerationen_US
dc.subjectStructure–activity relationship studiesen_US
dc.titleDiscovery of sultam-containing small-molecule disruptors of the huntingtin–calmodulin protein–protein interactionen_US
dc.typeArticleen_US
kusw.kuauthorKapadia, Khushboo
kusw.kuauthorMcDonald, Peter
kusw.kuauthorRoy, Anuradha
kusw.kuauthorMuma, Nancy A.
kusw.kudepartmentPharmacology and Toxicologyen_US
kusw.kudepartmentHigh-Throughput Screening Laboratoryen_US
dc.identifier.doi10.1007/s00044-020-02583-8en_US
kusw.oaversionScholarly/refereed, author accepted manuscripten_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.identifier.pmidPMC7906539en_US
dc.rights.accessrightsopenAccessen_US


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