Design, synthesis and efficacy of new small molecule therapeutics to impede myotonic dystrophy

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Summary/Abstract Many of the growing family of over 40 neuromuscular and neurodegenerative repeat expansion diseases, including myotonic dystrophy (DM), involve a strong RNA gain-of- function (GOF) mechanism with toxicity induced by expansion RNAs. In this mechanism, the expanded RNAs sequester RNA binding proteins (RBPs) leading to the disruption of multiple downstream RNA processing pathways. The reduction of the expanded RNAs to alleviate disease mechanism and downstream pathogenesis is therefore an attractive therapeutic approach. We have previously demonstrated promising small molecule efficacy including: (1) actinomycin D mediated selective reduction of transcription from expanded CTG repeats; (2) microtubule inhibitors mediated selective modulation of toxic CUG RNA levels; and (3) diamidines mediated reduction of toxic RNAs. While these results show promise, many of these compounds are toxic and display sub-optimal properties leading us to develop a new set of modified polycyclic compounds (MPCs). These compounds are based on three elements: a heterocyclic core; a benzimidazole side group; and functionalized end groups. Modifying each of these elements provides a large panel of potential compounds to aid in understanding mechanism of action and develop new drug candidates to address the urgent unmet therapeutic need in DM. Preliminary data for two of these MPCs shows robust rescue of splicing in both DM1 and DM2 cell lines in the nanomolar range with little associated toxicity or effects on cell viability as well as rescue of mis-splicing in 2 independent DM mouse models. In this proposal, we will use parallel in vitro and in vivo design-model-test cycles to systematically modify and evaluate compounds by focusing on replacement, testing and refinement of the three MPC elements (core, side and end groups). These data will provide a better understanding of their mechanism of action and be followed by testing of their therapeutic potential in DM patient-derived cell lines and animal models. The successful completion of this project will provide a new class of therapeutic small molecules, a better understanding of their mechanism of action and in vivo data from multiple animal models supporting their future therapeutic potential. Taken together this information will address the large unmet need for therapeutic approaches for DM and provide supporting data towards future clinical studies.