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