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

Autor:	Liu L; CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, California 90045, United States., Malagu K; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., Haughan AF; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., Khetarpal V; CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, California 90045, United States., Stott AJ; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., Esmieu W; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., Vater HD; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., Webster SJ; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., Van de Poël AJ; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., Clissold C; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., Cosgrove B; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., Sutton B; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., Spencer JA; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., Breccia P; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., Gancia E; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., Bonomo S; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., Ladduwahetty T; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., Lazari O; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., Patel H; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., Atton HC; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., Clifton S; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., Mota DM; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., Magnani D; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., O'Neill A; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., Stebbeds M; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., Macabuag N; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., Todd D; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., Herva ME; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., Mitchell P; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., Visser M; Charles River, Darwinweg 24, 2333 CR Leiden, The Netherlands., Compte Sancerni S; Charles River, Darwinweg 24, 2333 CR Leiden, The Netherlands., Grand Moursel L; Charles River, Darwinweg 24, 2333 CR Leiden, The Netherlands., da Silva M; Charles River, Darwinweg 24, 2333 CR Leiden, The Netherlands., Kritikou E; Charles River, Darwinweg 24, 2333 CR Leiden, The Netherlands., Heikkinen TT; Charles River, Microkatu 1, Kuopio 70210 Finland., Bolkvadze T; Charles River, Microkatu 1, Kuopio 70210 Finland., Fodale V; IRBM S.p.A., Pomezia, Roma 00071, Italy., Spadafora D; IRBM S.p.A., Pomezia, Roma 00071, Italy., Daldin M; IRBM S.p.A., Pomezia, Roma 00071, Italy., Bresciani A; IRBM S.p.A., Pomezia, Roma 00071, Italy., Mangette JE; Curia Global, Inc., Buffalo, New York 14203, United States., Doherty EM; CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, California 90045, United States., Lee MR; CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, California 90045, United States., Herbst T; CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, California 90045, United States., Monteagudo E; CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, California 90045, United States., Macdonald D; CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, California 90045, United States., Plotnikov NV; CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, California 90045, United States., Chambers M; Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, U.K., McAllister G; CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, California 90045, United States., Muňoz-Sanjuan I; CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, California 90045, United States., Dominguez C; CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, California 90045, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2023 Sep 28; Vol. 66 (18), pp. 13205-13246. Date of Electronic Publication: 2023 Sep 15.
DOI:	10.1021/acs.jmedchem.3c01173
Abstrakt:	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.
Databáze:	MEDLINE
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