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Competitive Microarray Screening Reveals Functional Ligands for the DHX15 RNA G-Quadruplex.
Peri R Prestwood1, Mo Yang1, Grace V Lewis1
1Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702-1201, United States.
ACS Medicinal Chemistry Letters
|June 19, 2024
Summary
Researchers identified a novel RNA G-quadruplex in DHX15 mRNA and developed a compound (F1) that inhibits its translation, offering a new strategy for cancer therapeutics targeting RNA.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- RNA molecules are emerging as critical targets for therapeutic intervention.
- Developing methods to identify RNA targets and their corresponding ligands is crucial for advancing medicine.
Purpose of the Study:
- To identify and validate RNA targets and ligands for therapeutic development.
- To discover novel small molecule inhibitors for cancer-relevant RNA targets.
Main Methods:
- Bioinformatic analysis to identify RNA G-quadruplex (rG4) structures in mRNA.
- Competitive small molecule microarray (SMM) assay for ligand screening.
- In vitro translation assays to assess target modulation.
Main Results:
- Identified a hairpin-containing rG4 in the 5' untranslated region of DHX15 mRNA.
- Discovered a small molecule (F1) that specifically binds to the DHX15 rG4 with a KD of 12.6 ± 1.0 μM.
- Demonstrated that F1 inhibits DHX15 mRNA translation by up to 57% (IC50 = 22.9 ± 3.8 μM).
Conclusions:
- The study successfully identified a novel RNA target (DHX15 rG4) and a specific inhibitor (F1).
- This work validates a new screening approach for developing RNA-targeted therapeutics.
- The findings provide a foundation for developing novel small molecule cancer therapeutics targeting RNA.
