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. 2022 Aug 8;21(10):736–762. doi: 10.1038/s41573-022-00521-4

Table 3.

Examples of small molecules that bind to RNAs implicated in neuromuscular and neurodegenerative diseases

Compound/institution Associated disease RNA target Mode of action Stage of development Activity Refs.

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Cugamycin/Scripps Research Institute

 Myotonic dystrophy type 1 r(CUG)exp in DMPK mRNA Displaces MBNL1 from binding to r(CUG)exp Early discovery Kd = 365 nM (for r(CUG)12); EC25 = 840 nM (rescued splicing defects) 278

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Synucleozid/Scripps Research Institute

 Parkinson disease Iron-responsive element in α-synuclein mRNA Inhibits ribosomal assembly and polysome loading onto α-synuclein mRNA Early discovery Kd = 1.5 μM; IC50 (neurons) = 0.5 μM 13

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Mitoxantrone/University of Washington, Seattle

 Alzheimer disease; frontotemporal dementia with parkinsonism-17 Exon 10–intron junction in MAPT pre-mRNA Inhibits binding of splicing machinery at the exon 10–intron junction; also inhibits a fungal group II intron277 Early discovery Kd <1 μM; EC50 = 700 nM (competition of binding with 25 nM pyrene–neomycin conjugate) 225,279

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Compound 9/Scripps Research Institute

 Alzheimer disease; frontotemporal dementia with parkinsonism-17 Exon 10–intron junction in MAPT pre-mRNA Inhibits binding of splicing machinery at the exon 10–intron junction Early discovery Kd = 4.9 μM; IC50 (transfected HeLa cells) = 10 μM; decreased 4R/3R ratio by ~50% in primary neurons at 40 μM 70,228

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Risdiplam/Roche and PTC Therapeutics

 SMA SMN2 pre-mRNA exon 7–intron junction Promotes exon inclusion by stabilizing the binding of the splicing machinery FDA approved Kd = 15 nM; EC1.5x (SMA patient-derived fibroblasts) = 7 nM 14

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Branaplam

 SMA; HD SMN2 pre-mRNA exon 7–intron junction Promotes exon inclusion by stabilizing the binding of the splicing machinery Phase I/II clinical trial (for SMA: NCT02268552; for HD: NCT05111249) EC50 (SMN ELISA in SMNΔ7 mouse myoblasts) = 20 nM 15

EC50, half maximal effective concentration; ELISA, enzyme-linked immunosorbent assay; HD, Huntington disease; IC50, half maximal inhibitory concentration; Kd, dissociation constant; SMA, spinal muscular atrophy; SMN, survival of motor neuron.