Rationally Designed Small Molecules That Target Both the DNA and RNA Causing Myotonic Dystrophy Type 1

Single-agent, single-target therapeutic approaches are often limited by a complex disease pathobiology. We report rationally designed, multi-target agents for myotonic dystrophy type 1 (DM1). DM1 originates in an abnormal expansion of CTG repeats (CTGexp) in the DMPK gene. The resultant expanded CUG...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2015-11, Vol.137 (44), p.14180-14189
Main Authors: Nguyen, Lien, Luu, Long M, Peng, Shaohong, Serrano, Julio F, Chan, H. Y. Edwin, Zimmerman, Steven C
Format: Article
Language:English
Subjects:
Animals
Disease Models, Animal
DNA - genetics
DNA - metabolism
Drosophila
Drug Design
HeLa Cells
Humans
Myotonic Dystrophy - drug therapy
Myotonic Dystrophy - genetics
Myotonic Dystrophy - pathology
RNA - biosynthesis
RNA - genetics
RNA - metabolism
Small Molecule Libraries - chemical synthesis
Small Molecule Libraries - chemistry
Small Molecule Libraries - pharmacology
Trinucleotide Repeat Expansion - drug effects
Trinucleotide Repeat Expansion - genetics
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Summary:Single-agent, single-target therapeutic approaches are often limited by a complex disease pathobiology. We report rationally designed, multi-target agents for myotonic dystrophy type 1 (DM1). DM1 originates in an abnormal expansion of CTG repeats (CTGexp) in the DMPK gene. The resultant expanded CUG transcript (CUGexp) identified as a toxic agent sequesters important proteins, such as muscleblind-like proteins (MBNL), undergoes repeat-associated non-ATG (RAN) translation, and potentially causes microRNA dysregulation. We report rationally designed small molecules that target the DM1 pathobiology in vitro in three distinct ways by acting simultaneously as transcription inhibitors, by inhibiting aberrant protein binding to the toxic RNA, and by acting as RNase mimics to degrade the toxic RNA. In vitro, the agents are shown to (1) bind CTGexp and inhibit formation of the CUGexp transcript, (2) bind CUGexp and inhibit sequestration of MBNL1, and (3) cleave CUGexp in an RNase-like manner. The most potent compounds are capable of reducing the levels of CUGexp in DM1 model cells, and one reverses two separate CUGexp-induced phenotypes in a DM1 Drosophila model.
ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.5b09266