Target-Directed Approaches for Screening Small Molecules against RNA Targets

Abstract

RNA molecules have a variety of cellular functions that can drive disease pathologies. They are without a doubt one of the most intriguing yet controversial small-molecule drug targets. The ability to widely target RNA with small molecules could be revolutionary, once the right tools, assays, and targets are selected, thereby defining which biomolecules are targetable and what constitutes drug-like small molecules. Indeed, approaches developed over the past 5–10 years have changed the face of small molecule–RNA targeting by addressing historic concerns regarding affinity, selectivity, and structural dynamics. Presently, selective RNA–protein complex stabilizing drugs such as branaplam and risdiplam are in clinical trials for the modulation of SMN2 splicing, compounds identified from phenotypic screens with serendipitous outcomes. Fully developing RNA as a druggable target will require a target engagement-driven approach, and evolving chemical collections will be important for the industrial development of this class of target. In this review we discuss target-directed approaches that can be used to identify RNA-binding compounds and the chemical knowledge we have today of small-molecule RNA binders.

Fragment‐Based Drug Discovery for RNA Targets

“…[4] Additionally, only about 1.5 % of the human genome codes for proteins while more than 50 % are being transcribed into RNA, suggesting that non-coding RNA (ncRNA) may provide a promising druggable alternative. [4,6] Examples of these are riboswitches which regulate the expression of downstream genes through binding of small molecules, [7,8] as well as tRNA and rRNA involved in the translation of proteins. [9] As more attention is paid to RNA as a target, technologies for screening and structural determination are also developing, providing new opportunities for targeting diseases through RNA instead of proteins.…”

“…[58,61] Looking at privileged structures, the Disney group has provided an initial overview on privileged small-molecule scaffolds from where it may be possible to draw inspiration when designing RNA-targeting fragment libraries (Figure 11). [4,59,63] They have determined the benzimidazole scaffold ( 14) as a privileged scaffold and built-up a small-molecule library against RNA based on this. [59] More recently, the Disney group has presented additional potential privileged small-molecule scaffolds based on literature results, consisting of benzimidazoles (14), imidazoles (15), phenyl imidazolines (16), indoles (17), N-substituted carbazoles (18), alkyl pyridinium scaffolds (19), 2-amino-pyridines (20), 2amino-quinolines ( 21), 1,8-diamino-2,7-naphtyridines ( 22), and 2-aminopyrimidines (23).…”

Drug Screening and Drug Repositioning as Promising Therapeutic Approaches for Spinal Muscular Atrophy Treatment

“…Therefore, RG7800 was optimized developing a new oral drug, RG7916, known as Risdiplam, which was tested in different cell lines and animal models (mice, rats, and monkeys) (Poirier et al, 2018;Ratni et al, 2018). Risdiplam is currently under evaluation in the four clinical studies mentioned above in Spinal Muscular Atrophy Approved Drugs (Kletzl et al, 2019;Haniff et al, 2020).…”

In Vitro Evaluation of Bis-3-Chloropiperidines as RNA Modulators Targeting TAR and TAR-Protein Interaction

“…The last few years have witnessed a remarkable surge of interest in RNA as a putative therapeutic and research tool, which has led to a greater understanding of structure/function relationships and the discovery of fundamental roles in infection, inflammation, and other disease conditions [ 1 , 2 ]. Likewise, renewed attention has been devoted to studying the roles of RNA-protein interactions in the aforementioned conditions.…”