Rationally designed inhibitors of the Musashi protein-RNA interaction by hotspot mimicry

Area of Science:

• Biochemistry and Molecular Biology
• Drug Discovery and Development

Background:

• RNA-binding proteins (RBPs) are critical post-transcriptional regulators governing gene expression and numerous biological processes.
• Dysregulation of RBPs, such as Musashi proteins (MSI1/MSI2), is implicated in cancer progression due to their roles in mRNA stability and translation.

Approach:

• A novel strategy was developed to extract a "hotspot pharmacophore" from protein-RNA complex structures.
• This pharmacophore serves as a template for designing small-molecule inhibitors and assessing their selectivity.
• The approach was validated by designing and synthesizing inhibitors targeting MSI1 and MSI2.

Key Points:

• The developed MSI1/MSI2 inhibitors demonstrated specificity and activity across biochemical, biophysical, and cellular assays.
• This study extends the "hotspot" concept from protein-protein to protein-RNA interactions, highlighting the druggability of RBP surfaces.
• It represents a significant advancement in rationally designing inhibitors for non-enzymatic RBPs.

Conclusions:

• The
• hotspot pharmacophore
• strategy offers a generalizable method for developing inhibitors against various RBPs.
• This approach can also inform the design of PROTACs for targeted RBP degradation and predict potential off-target interactions.