title: Selective inhibition of MBNL1-CCUG interaction by small molecules toward potential therapeutic agents for myotonic dystrophy type 2 (DM2).
abstract: Myotonic dystrophy type 2 (DM2) is an incurable neuromuscular disease caused by expanded CCUG repeats that may exhibit toxicity by sequestering the splicing regulator MBNL1. A series of triaminotriazine- and triaminopyrimidine-based small molecules (ligands 1-3) were designed, synthesized and tested as inhibitors of the MBNL1-CCUG interaction. Despite the structural similarities of the triaminotriazine and triaminopyrimidine units, the triaminopyrimidine-based ligands bind with low micromolar affinity to CCUG repeats (K(d) ∼ 0.1-3.6 µM) whereas the triaminotriazine ligands do not bind CCUG repeats. Importantly, these simple and small triaminopyrimidine ligands exhibit both strong inhibition (K(i) ∼ 2 µM) of the MBNL1-CCUG interaction and high selectivity for CCUG repeats over other RNA targets. These experiments suggest these compounds are potential lead agents for the treatment of DM2.
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Chun-Ho
authors.initials: CH
authors.lastname: Wong
authors.forename: Yuan
authors.initials: Y
authors.lastname: Fu
authors.forename: Sreenivasa Rao
authors.initials: SR
authors.lastname: Ramisetty
authors.forename: Anne M
authors.initials: AM
authors.lastname: Baranger
authors.forename: Steven C
authors.initials: SC
authors.lastname: Zimmerman
mesh_terms: D000166:Acridines / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D004247:DNA / Q000737:chemistry; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D020967:Myotonic Disorders / Q000188:drug therapy; D009223:Myotonic Dystrophy; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012313:RNA / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012091:Repetitive Sequences, Nucleic Acid
chemical_list: D000166:Acridines; D007364:Intercalating Agents; D008024:Ligands; D011743:Pyrimidines; D016601:RNA-Binding Proteins; D012313:RNA; D004247:DNA