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