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Development of Macrocyclic PRMT5–Adaptor Protein Interaction Inhibitors
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2022-11-15 , DOI: 10.1021/acs.jmedchem.2c01273
Adrian Krzyzanowski 1, 2 , Lea Marie Esser 3 , Anthony Willaume 4 , Renaud Prudent 4 , Christoph Peter 3 , Peter 't Hart 5 , Herbert Waldmann 1, 2
Affiliation  

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 (Ki = 66 nM), which selectively inhibits the interaction of PRMT5 with the adaptor proteins RioK1 and pICln (IC50 = 654 nM) but not with the alternative adaptor protein MEP50. The inhibitor is a promising tool for further biological investigation of this intriguing protein interface.

中文翻译:

大环 PRMT5-衔接子蛋白相互作用抑制剂的开发

PRMT5-MEP50 甲基转移酶是抗癌药物发现的主要目标,其与不同调节蛋白相互作用的调节剂需求量很大,因为它们调节 PRMT5 底物选择性。我们描述了 PRMT5/衔接蛋白 PPI 抑制剂的开发策略,其中包括基于 PRMT5 与其衔接蛋白 RioK1 相互作用的基序设计和合成大环肽。在对不同大环大小和环化连接进行初步探索后,对肽库的分析确定了氨基酸结构变化的热点。将非蛋白质氨基酸掺入大环肽导致有效的环状 PRMT5 结合肽 ( K i= 66 nM),它选择性地抑制 PRMT5 与衔接蛋白 RioK1 和 pICln (IC 50 = 654 nM)的相互作用,但不抑制与替代衔接蛋白 MEP50 的相互作用。该抑制剂是对这种有趣的蛋白质界面进行进一步生物学研究的有前途的工具。
更新日期:2022-11-15
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