Selective inhibition of MBNL1-CCUG interaction by small molecules toward potential therapeutic agents for myotonic dystrophy type 2 (DM2)

Chun Ho Wong, Yuan Fu, Sreenivasa Rao Ramisetty, Anne M. Baranger, Steven C. Zimmerman

Research output: Contribution to journalArticlepeer-review

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 (Kd∼0.1-3.6M) whereas the triaminotriazine ligands do not bind CCUG repeats. Importantly, these simple and small triaminopyrimidine ligands exhibit both strong inhibition (Ki∼2M) 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.

Original languageEnglish (US)
Pages (from-to)8881-8890
Number of pages10
JournalNucleic acids research
Volume39
Issue number20
DOIs
StatePublished - Nov 2011

ASJC Scopus subject areas

  • Genetics

Fingerprint Dive into the research topics of 'Selective inhibition of MBNL1-CCUG interaction by small molecules toward potential therapeutic agents for myotonic dystrophy type 2 (DM2)'. Together they form a unique fingerprint.

Cite this