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