Development of Macrocyclic PRMT5-Adaptor Protein Interaction Inhibitors

Area of Science:

• Oncology
• Biochemistry
• Medicinal Chemistry

Background:

• Protein arginine methyltransferase 5 (PRMT5) is a crucial target for anticancer drug development.
• Modulators of PRMT5 interactions are needed to control its substrate selectivity.
• PRMT5's interaction with adaptor proteins like MEP50, RioK1, and pICln is central to its function.

Purpose of the Study:

• To develop a PRMT5/adaptor protein protein-protein interaction (PPI) inhibitor.
• To design and synthesize macrocyclic peptides targeting the PRMT5-RioK1 interaction motif.
• To identify potent and selective inhibitors for further biological investigation.

Main Methods:

• Design and synthesis of a macrocyclic peptide library based on the PRMT5-RioK1 interaction.
• Exploration of various macrocycle sizes and cyclization strategies.
• Structure-activity relationship (SAR) analysis to identify key amino acid variations.
• Incorporation of nonproteinogenic amino acids to enhance binding affinity and selectivity.

Main Results:

• Identification of a potent cyclic PRMT5 binding peptide with a dissociation constant (Kd) of 66 nM.
• Demonstration of selective inhibition of PRMT5 interaction with adaptor proteins RioK1 and pICln (IC50 = 654 nM).
• Lack of inhibition against the PRMT5-MEP50 interaction, highlighting selectivity.

Conclusions:

• A novel macrocyclic peptide inhibitor effectively targets the PRMT5 methyltransferase.
• The developed inhibitor shows selectivity for PRMT5 interactions with specific adaptor proteins.
• This inhibitor represents a valuable tool for exploring the biological roles of the PRMT5 protein interface in cancer research.