Studying a Drug-like, RNA-Focused Small Molecule Library Identifies Compounds That Inhibit RNA Toxicity in Myotonic Dystrophy

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 in cellulo 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 banding 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)(exp)) that causes myotonic dystrophy type 1. Hit compounds bind the target in cellulo, as determined by the target identification approach I Competitive Chemical Cross Linking and Isolation by, Pull-down (C-ChemCLIP), and selectively in-Trove several disease:associated defects. The best compounds identified froth our 320-member library are, More potent in cellulo 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.