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Using In Vitro and In-cell SHAPE to Investigate Small Molecule Induced Pre-mRNA Structural Changes
Published on: January 30, 2019
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Rationally designed inhibitors of the Musashi protein-RNA interaction by hotspot mimicry
Nan Bai1,2, Yusuf Adeshina1,3, Igor Bychkov4
1Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia PA 19111.
Research Square
|January 30, 2023
Summary
Researchers developed a new method to design small-molecule inhibitors for RNA-binding proteins (RBPs). This approach successfully created specific inhibitors for Musashi proteins (MSI1/MSI2), which are crucial in cancer.
Area of Science:
- Biochemistry and Molecular Biology
- Drug Discovery and Development
Background:
- RNA-binding proteins (RBPs) are critical regulators of gene expression, influencing numerous biological processes.
- Dysregulation of RBPs like Musashi proteins (MSI1/MSI2) is linked to cancer progression.
- Targeting non-enzymatic RBPs presents a significant challenge in drug development.
Approach:
- Developed a strategy to extract
- hotspot pharmacophores
- from protein-RNA complex structures.
- Utilized these pharmacophores as templates for designing small-molecule inhibitors.
- Applied the approach to design and validate inhibitors for MSI1 and MSI2 proteins.
Key Points:
- Successfully designed and synthesized novel small-molecule inhibitors targeting MSI1 and MSI2.
- Demonstrated specificity and activity of these inhibitors across biochemical, biophysical, and cellular assays.
- Extended the
- hotspot
- concept from protein-protein to protein-RNA interactions.
Conclusions:
- The study validates the
- hotspot pharmacophore
- strategy for targeting RBPs, supporting their
- druggability
- .
- This approach offers a generalizable method for developing inhibitors against various RBPs.
- Compounds designed via this method could also be utilized in developing targeted protein degraders (PROTACs).
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