Studying a Drug-like, RNA-Focused Small Molecule Library Identifies Compounds That Inhibit RNA Toxicity in Myotonic Dystrophy Suzanne G. Rzuczek Mark R. Southern Matthew D. Disney 10.1021/acschembio.5b00430.s001 https://acs.figshare.com/articles/journal_contribution/Studying_a_Drug_like_RNA_Focused_Small_Molecule_Library_Identifies_Compounds_That_Inhibit_RNA_Toxicity_in_Myotonic_Dystrophy/2097028 There are many RNA targets in the transcriptome to which small molecule chemical probes and lead therapeutics are desired. However, identifying compounds that bind and modulate RNA function <i>in cellulo</i> is difficult. Although rational design approaches have been developed, they are still in their infancies and leave many RNAs “undruggable”. In an effort to develop a small molecule library that is biased for binding RNA, we computationally identified “drug-like” compounds from screening collections that have favorable properties for binding RNA and for suitability as lead drugs. As proof-of-concept, this collection was screened for binding to and modulating the cellular dysfunction of the expanded repeating RNA (r­(CUG)<sup>exp</sup>) that causes myotonic dystrophy type 1. Hit compounds bind the target <i>in cellulo</i>, as determined by the target identification approach Competitive Chemical Cross-Linking and Isolation by Pull-down (C-ChemCLIP), and selectively improve several disease-associated defects. The best compounds identified from our 320-member library are more potent <i>in cellulo</i> than compounds identified by high-throughput screening (HTS) campaigns against this RNA. Furthermore, the compound collection has a higher hit rate (9% compared to 0.01–3%), and the bioactive compounds identified are not charged; thus, RNA can be “drugged” with compounds that have favorable pharmacological properties. Finally, this RNA-focused small molecule library may serve as a useful starting point to identify lead “drug-like” chemical probes that affect the biological (dys)­function of other RNA targets by direct target engagement. 2015-12-18 00:00:00 Molecule Library Identifies Compounds compound Inhibit RNA Toxicity causes myotonic dystrophy type 1. molecule library RNA targets HTS target identification approach molecule chemical probes binding RNA