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.

SUBMITTER: Wong CH 

PROVIDER: S-EPMC3203617 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature