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

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

  • J Med Chem. 2023 Sep 28;66(18):13205-13246. doi: 10.1021/acs.jmedchem.3c01173.
Longbin Liu 1 Karine Malagu 2 Alan F Haughan 2 Vinod Khetarpal 1 Andrew J Stott 2 William Esmieu 2 Huw D Vater 2 Stephen J Webster 2 Amanda J Van de Poël 2 Cole Clissold 2 Brett Cosgrove 2 Benjamin Sutton 2 Jonathan A Spencer 2 Perla Breccia 2 Emanuela Gancia 2 Silvia Bonomo 2 Tammy Ladduwahetty 2 Ovadia Lazari 2 Hiral Patel 2 Helen C Atton 2 Steve Clifton 2 Daniel M Mota 2 Dario Magnani 2 Amy O'Neill 2 Marta Stebbeds 2 Natsuko Macabuag 2 Daniel Todd 2 Maria E Herva 2 Philip Mitchell 2 Mijke Visser 3 Sara Compte Sancerni 3 Laure Grand Moursel 3 Marta da Silva 3 Eva Kritikou 3 Taneli T Heikkinen 4 Tamuna Bolkvadze 4 Valentina Fodale 5 Debora Spadafora 5 Manuel Daldin 5 Alberto Bresciani 5 John E Mangette 6 Elizabeth M Doherty 1 Matthew R Lee 1 Todd Herbst 1 Edith Monteagudo 1 Douglas Macdonald 1 Nikolay V Plotnikov 1 Mark Chambers 2 George McAllister 1 Ignacio Muňoz-Sanjuan 1 Celia Dominguez 1
Affiliations

Affiliations

  • 1 CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, California 90045, United States.
  • 2 Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K.
  • 3 Charles River, Darwinweg 24, 2333 CR Leiden, The Netherlands.
  • 4 Charles River, Microkatu 1, Kuopio 70210 Finland.
  • 5 IRBM S.p.A., Pomezia, Roma 00071, Italy.
  • 6 Curia Global, Inc., Buffalo, New York 14203, United States.
Abstract

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.

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