Development of Macrocyclic PRMT5-Adaptor Protein Interaction Inhibitors.

ABSTRACT: The PRMT5-MEP50 methyltransferase is a major target for anticancer drug discovery, and modulators of its interactions with different regulatory proteins are in high demand because they modulate PRMT5 substrate selectivity. We describe a strategy for the development of a PRMT5/adaptor protein PPI inhibitor, which includes the design and synthesis of macrocyclic peptides based on the motif for the interaction of PRMT5 with its adaptor protein RioK1. After the initial exploration of different macrocycle sizes and cyclization linkages, analysis of a peptide library identified hot spots for the variation of the amino acid structure. The incorporation of nonproteinogenic amino acids into the macrocyclic peptide led to a potent cyclic PRMT5 binding peptide (K_i = 66 nM), which se

SUBMITTER: Krzyzanowski A 

PROVIDER: S-EPMC9706563 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature