Key result
Triaminopyrimidine-based small molecules selectively bind CCUG repeats and strongly inhibit the MBNL1-CCUG interaction with a Ki of approximately 2 μM, serving as potential lead agents for DM2.
Effect estimate: Ki ~2 μM
Triaminopyrimidine-based small molecules demonstrate strong, selective inhibition of the MBNL1-CCUG interaction, representing potential lead agents for myotonic dystrophy type 2.
Triaminopyrimidine ligands advance DM2-targeted chemistry; leaves open cellular efficacy and in vivo validation.
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.
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Wong et al. (2011) studied Myotonic dystrophy type 2 (DM2) (in vitro model). Triaminopyrimidine-based small molecules (ligands 2 and 3) was evaluated on Inhibition of MBNL1-CCUG interaction (Ki) (Ki ~2 μM). Triaminopyrimidine-based small molecules selectively bind CCUG repeats and strongly inhibit the MBNL1-CCUG interaction with a Ki of approximately 2 μM, serving as potential lead agents for DM2.
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