A Potent Inhibitor of Protein Sequestration by Expanded Triplet (CUG) Repeats that Shows Phenotypic Improvements in a Drosophila Model of Myotonic Dystrophy
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AbstractMyotonic dystrophy is the most common form of adult-onset muscular dystrophy, originating in a CTG repeat expansion in the DMPK gene. The expanded CUG transcript sequesters MBNL1, a key regulator of alternative splicing, leading to the misregulation of numerous pre-mRNAs. We report an RNA-targeted agent as a possible lead compound for the treatment of myotonic dystrophy type1 (DM1) that reveals both the promise and challenges for this type of small-molecule approach. The agent is a potent inhibitor of the MBNL1-rCUG complex with an inhibition constant (K-i) of 25 +/- 8nm, and is also relatively nontoxic to HeLa cells, able to dissolve nuclear foci, and correct the insulin receptor splicing defect in DM1 model cells. Moreover, treatment with this compound improves two separate disease phenotypes in a Drosophila model of DM1: adult external eye degeneration and larval crawling defect. However, the compound has a relatively low maximum tolerated dose in mice, and its cell uptake may be limited, providing insight into directions for future development.
All Author(s) ListLuu LM, Nguyen L, Peng SH, Lee J, Lee HY, Wong CH, Hergenrother PJ, Chan HYE, Zimmerman SC
Journal nameChemMedChem
Year2016
Month7
Day5
Volume Number11
Issue Number13
PublisherWILEY-V C H VERLAG GMBH
Pages1428 - 1435
ISSN1860-7179
LanguagesEnglish-United Kingdom
KeywordsClick chemistry; Drosophila model; Myotonic dystrophy; RNA recognition; RNA-protein inhibitor
Web of Science Subject CategoriesChemistry, Medicinal; Pharmacology & Pharmacy

Last updated on 2021-09-10 at 00:30