Target-Directed Approaches for Screening Small Molecules against RNA Targets

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Molecular Biology

Background:

• RNA molecules play crucial roles in cellular functions and disease.
• RNA presents unique challenges and opportunities as a small-molecule drug target.
• Historically, targeting RNA with small molecules has faced hurdles in affinity, selectivity, and dynamics.

Purpose of the Study:

• To review target-directed approaches for identifying RNA-binding compounds.
• To discuss the current chemical knowledge of small-molecule RNA binders.
• To highlight the evolution of small molecule-RNA targeting strategies.

Main Methods:

• Review of recent literature on small molecule-RNA interactions.
• Analysis of target-directed approaches in RNA drug discovery.
• Discussion of chemical collections and their role in industrial development.

Main Results:

• Significant progress has been made in small molecule-RNA targeting over the past 5-10 years.
• Selective RNA-protein complex stabilizing drugs (e.g., branaplam, risdiplam) are in clinical trials for splicing modulation.
• Phenotypic screening has led to serendipitous discoveries of RNA-targeting compounds.

Conclusions:

• Developing RNA as a druggable target necessitates a target engagement-driven approach.
• Evolving chemical collections is crucial for the industrial development of RNA-targeted therapeutics.
• Further research into target-directed strategies and chemical knowledge will advance RNA-based drug discovery.