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DOI 10.1021/acs.jmedchem.3c01173

Медицинская библиотека · Journal of medicinal chemistry · 2023

Identification and Optimization of RNA-Splicing Modulators as Huntingtin Protein-Lowering Agents for the Treatment of Huntington's Disease.

Liu Longbin, Malagu Karine, Haughan Alan F, Khetarpal Vinod, Stott Andrew J, Esmieu William, Vater Huw D, Webster Stephen J, Van de Poël Amanda J, Clissold Cole, Cosgrove Brett, Sutton Benjamin, Spencer Jonathan A, Breccia Perla, Gancia Emanuela, Bonomo Silvia, Ladduwahetty Tammy, Lazari Ovadia, Patel Hiral, Atton Helen C, Clifton Steve, Mota Daniel M, Magnani Dario, O'Neill Amy, Stebbeds Marta, Macabuag Natsuko, Todd Daniel, Herva Maria E, Mitchell Philip, Visser Mijke, Compte Sancerni Sara, Grand Moursel Laure, da Silva Marta, Kritikou Eva, Heikkinen Taneli T, Bolkvadze Tamuna, Fodale Valentina, Spadafora Debora, Daldin Manuel, Bresciani Alberto, Mangette John E, Doherty Elizabeth M, Lee Matthew R, Herbst Todd, Monteagudo Edith, Macdonald Douglas, Plotnikov Nikolay V, Chambers Mark, McAllister George, Muňoz-Sanjuan Ignacio, Dominguez Celia

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Аннотация

Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene. We report the design of a series of HTT pre-mRNA splicing modulators that lower huntingtin (HTT) protein, including the toxic mutant huntingtin (mHTT), by promoting insertion of a pseudoexon containing a premature termination codon at the exon 49-50 junction. The resulting transcript undergoes nonsense-mediated decay, leading to a reduction of HTT mRNA transcripts and protein levels. The starting benzamide core was modified to pyrazine amide and further optimized to give a potent, CNS-penetrant, and orally bioavailable HTT-splicing modulator 27. This compound reduced canonical splicing of the HTT RNA exon 49-50 and demonstrated significant HTT-lowering in both human HD stem cells and mouse BACHD models. Compound 27 is a structurally diverse HTT-splicing modulator that may help understand the mechanism of adverse effects such as peripheral neuropathy associated with branaplam.

Для цитирования: Liu Longbin, Malagu Karine, Haughan Alan F, Khetarpal Vinod, Stott Andrew J, Esmieu William, Vater Huw D, Webster Stephen J, Van de Poël Amanda J, Clissold Cole, Cosgrove Brett, Sutton Benjamin, Spencer Jonathan A, Breccia Perla, Gancia Emanuela, Bonomo Silvia, Ladduwahetty Tammy, Lazari Ovadia, Patel Hiral, Atton Helen C, Clifton Steve, Mota Daniel M, Magnani Dario, O'Neill Amy, Stebbeds Marta, Macabuag Natsuko, Todd Daniel, Herva Maria E, Mitchell Philip, Visser Mijke, Compte Sancerni Sara, Grand Moursel Laure, da Silva Marta, Kritikou Eva, Heikkinen Taneli T, Bolkvadze Tamuna, Fodale Valentina, Spadafora Debora, Daldin Manuel, Bresciani Alberto, Mangette John E, Doherty Elizabeth M, Lee Matthew R, Herbst Todd, Monteagudo Edith, Macdonald Douglas, Plotnikov Nikolay V, Chambers Mark, McAllister George, Muňoz-Sanjuan Ignacio, Dominguez Celia. Identification and Optimization of RNA-Splicing Modulators as Huntingtin Protein-Lowering Agents for the Treatment of Huntington's Disease.. Journal of medicinal chemistry. 2023. DOI: 10.1021/acs.jmedchem.3c01173.

Предметные рубрики MeSH

Huntington DiseaseAnimalsHumansHuntingtin ProteinRNA SplicingMiceStructure-Activity RelationshipBenzamides
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