Targeting strategies for modulating pre-mRNA splicing with small molecules: Recent advances

Area of Science:

• Pharmacology and Molecular Biology
• Drug Discovery and Development
• RNA Biology

Background:

• The therapeutic modulation of pre-mRNA splicing using small molecules was validated by the FDA approval of risdiplam in 2020.
• Significant advancements in understanding RNA processing and regulatory networks have occurred since the initial discovery of risdiplam precursors.
• The field is actively pursuing novel splicing-modulating drugs due to these evolving insights and technologies.

Purpose of the Study:

• To compile and summarize small molecules developed since 2020 that modulate pre-mRNA splicing.
• To categorize these new molecules based on their biological targets.
• To provide an overview of the current landscape of splicing-modulating drug discovery.

Main Methods:

• Literature review of scientific publications and drug discovery databases.
• Categorization of identified small molecules by their targeted RNA processing pathways or regulatory networks.
• Summary of the discovery, design, and development status of these molecules.

Main Results:

• Identification and summarization of numerous small molecules discovered since 2020 aimed at altering pre-mRNA splicing.
• Classification of these molecules according to their specific biological targets within RNA processing.
• Highlighting the progression of drug development in this area, informed by new mechanistic insights.

Conclusions:

• The discovery and development of small molecules to modulate pre-mRNA splicing remain a dynamic and expanding field.
• Recent advancements offer more targeted therapeutic strategies for splicing-related disorders.
• Continued research is crucial for translating these novel molecules into clinical applications.