title: From dynamic combinatorial 'hit' to lead: in vitro and in vivo activity of compounds targeting the pathogenic RNAs that cause myotonic dystrophy.
abstract: The myotonic dystrophies (DM) are human diseases in which the accumulation of toxic RNA (CUG or CCUG) repeats in the cell causes sequestration of splicing factors, including MBNL1, leading to clinical symptoms such as muscle wasting and myotonia. We previously used Dynamic Combinatorial Chemistry to identify the first compounds known to inhibit (CUG)-MBNL1 binding in vitro. We now report transformation of those compounds into structures with activity in vivo. Introduction of a benzo[g]quinoline substructure previously unknown in the context of RNA recognition, as well as other modifications, provided several molecules with enhanced binding properties, including compounds with strong selectivity for CUG repeats over CAG repeats or CAG-CUG duplex RNA. Compounds readily penetrate cells, and improve luciferase activity in a mouse myoblast assay in which enzyme function is coupled to a release of nuclear CUG-RNA retention. Most importantly, two compounds are able to partially restore splicing in a mouse model of DM1.
authors.affiliation: Department of Chemistry, University of Rochester, Rochester, NY 14642, USA.
authors.forename: Leslie O
authors.initials: LO
authors.lastname: Ofori
authors.forename: Jason
authors.initials: J
authors.lastname: Hoskins
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nakamori
authors.forename: Charles A
authors.initials: CA
authors.lastname: Thornton
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Miller
mesh_terms: D000818:Animals; D002460:Cell Line; D020650:Combinatorial Chemistry Techniques; D007700:Kinetics; D051379:Mice; D009223:Myotonic Dystrophy / Q000235:genetics*; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D012313:RNA / Q000737:chemistry*; D012326:RNA Splicing; D016601:RNA-Binding Proteins / Q000378:metabolism; D013816:Thermodynamics; D018911:Trinucleotide Repeats
chemical_list: D011804:Quinolines; D016601:RNA-Binding Proteins; D012313:RNA