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Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat in exon 1 of the huntingtin () gene. We report the design of a series of 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 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 -splicing modulator . This compound reduced canonical splicing of the RNA exon 49-50 and demonstrated significant HTT-lowering in both human HD stem cells and mouse BACHD models. Compound is a structurally diverse -splicing modulator that may help understand the mechanism of adverse effects such as peripheral neuropathy associated with branaplam.
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| http://dx.doi.org/10.1021/acs.jmedchem.3c01173 | DOI Listing |
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