Abstract:
:Myotonic 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 type 1 (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 (Ki ) of 25±8 nm, 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.
journal_name
ChemMedChemjournal_title
ChemMedChemauthors
Luu LM,Nguyen L,Peng S,Lee J,Lee HY,Wong CH,Hergenrother PJ,Chan HY,Zimmerman SCdoi
10.1002/cmdc.201600081subject
Has Abstractpub_date
2016-07-05 00:00:00pages
1428-35issue
13eissn
1860-7179issn
1860-7187journal_volume
11pub_type
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