2. Academic Validation
  3. 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.
PMID: 37712656 DOI: 10.1021/acs.jmedchem.3c01173
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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