%0 Journal Article
%A Rzuczek, Suzanne G.
%A Southern, Mark R.
%A Disney, Matthew D.
%D 2015
%T Studying a Drug-like, RNA-Focused Small Molecule Library
Identifies Compounds That Inhibit RNA Toxicity in Myotonic Dystrophy
%U 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
%R 10.1021/acschembio.5b00430.s001
%2 https://acs.figshare.com/ndownloader/files/3730270
%K Molecule Library Identifies Compounds
%K compound
%K Inhibit RNA Toxicity
%K causes myotonic dystrophy type 1.
%K molecule library
%K RNA targets
%K HTS
%K target identification approach
%K molecule chemical probes
%K binding RNA
%X 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
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)exp) that
causes myotonic dystrophy type 1. Hit compounds bind the target in cellulo, 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 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.
%I ACS Publications