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A Potent Inhibitor of Protein Sequestration by Expanded Triplet (CUG) Repeats that Shows Phenotypic Improvements in a Drosophila Model of Myotonic Dystrophy
Author(s) -
Luu Long M.,
Nguyen Lien,
Peng Shaohong,
Lee JuYeon,
Lee Hyang Yeon,
Wong ChunHo,
Hergenrother Paul J.,
Chan H. Y. Edwin,
Zimmerman Steven C.
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600081
Subject(s) - myotonic dystrophy , rna splicing , biology , phenotype , trinucleotide repeat expansion , microbiology and biotechnology , genetics , gene , muscular dystrophy , small molecule , rna , allele
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 ( K i ) of 25±8 n m , 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.