We used bioinformatics analyses and computational chemistry techniques such as bespoke multi-parameter optimization for each gene family, combined with crowdsourcing efforts and human curation, to create a chemogenomic library of well-defined, selective small molecule pharmacological agents that cover over a thousand biological targets. A chemogenomic hit in a phenotypic screen may suggest that the annotated target(s) of that pharmacological tool are involved in perturbing the observable phenotype. In conjunction with other technologies such as RNAi and CRISPR, chemogenomic screening provides opportunities to discover new disease-relevant targets. A hit in the screen also suggests that the target is amenable to functional pharmacological modulation so providing opportunities to accelerate small molecule drug discovery or unearth mechanisms that enhance or synergize with other therapeutic modalities. Type 1 Myotonic Dystrophy (DM1) is caused by an expansion (CUG)n repeat in the DMPK gene that sequesters the RNA binding protein Muscleblind-like 1 (MBNL1) leading to a loss of its normal splicing function. MBNL1 overexpression has been shown to rescue splicing defects in the DM1 mouse model, although no small molecule or drug target for increasing MBNL1 expression has been identified. We used gene editing to successfully engineer a fluorescent tag into the endogenous MBNL1 locus and established a flow cytometry-based high-throughput screening system for the identification of MBNL1 up-regulators. We screened the chemogenomic set in this assay and identified several small molecule pharmacological modulators that increased MBNL1 expression and rescued the splicing defects caused by (CUG)n repeats. Additionally, these results further our understanding of MBNL1 up-regulation mechanisms in DM1 and help identify new therapeutic targets and drug candidates benefiting DM patients.

Chemogenomic screening identifies small molecule up-regulators of MBNL1 for the treatment of type 1 myotonic dystrophy

251st National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.