Rationally Designed Small Molecules That Target Both the DNA and RNA Causing Myotonic Dystrophy Type 1

Single-agent, single-target therapeutic approaches are often limited by a complex disease pathobiology. We report rationally designed, multi-target agents for myotonic dystrophy type 1 (DM1). DM1 originates in an abnormal expansion of CTG repeats (CTG^exp) in the <i>DMPK</i> gene. The resultant expanded CUG transcript (CUG^exp) identified as a toxic agent sequesters important proteins, such as muscleblind-like proteins (MBNL), undergoes repeat-associated non-ATG (RAN) translation, and potentially causes microRNA dysregulation. We report rationally designed small molecules that target the DM1 pathobiology <i>in vitro</i> in three distinct ways by acting simultaneously as transcription inhibitors, by inhibiting aberrant protein binding to the toxic RNA, and by acting as RNase mimics to degrade the toxic RNA. <i>In vitro</i>, the agents are shown to (1) bind CTG^exp and inhibit formation of the CUG^exp transcript, (2) bind CUG^exp and inhibit sequestration of MBNL1, and (3) cleave CUG^exp in an RNase-like manner. The most potent compounds are capable of reducing the levels of CUG^exp in DM1 model cells, and one reverses two separate CUG^exp-induced phenotypes in a DM1 Drosophila model