Structure, Function, and Activity of Small Molecule and Peptide Inhibitors of Protein Arginine Methyltransferase 1,Journal of Medicinal Chemistry

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Structure, Function, and Activity of Small Molecule and Peptide Inhibitors of Protein Arginine Methyltransferase 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-09 , DOI: 10.1021/acs.jmedchem.4c00490
Thordur Hendrickson-Rebizant _{1,

2} , Sadhana R N Sudhakar _{2,

3} , Michael J Rowley ₄ , Adam Frankel ₄ , James R Davie _{2,

3} , Ted M Lakowski _{1,

2}

Affiliation

Protein arginine N-methyltransferases (PRMT) are a family of S-adenosyl-l-methionine (SAM)-dependent enzymes that transfer methyl-groups to the ω-N of arginyl residues in proteins. PRMTs are involved in regulating gene expression, RNA splicing, and other activities. PRMT1 is responsible for most cellular arginine methylation, and its dysregulation is involved in many cancers. Accordingly, many groups have targeted PRMT1 using small molecules and peptide inhibitors. In this Perspective, we discuss the structure and function of selected peptide and small molecule inhibitors of PRMT1. We examine inhibitors that target the substrate arginyl peptide, SAM, or both binding sites, and the type of inhibition that results. Small molecules, and peptides that are bisubstrate, and/or PRMT transition state mimic inhibitors as well as inhibitors that alkylate PRMTs will be discussed. We define a structure–activity relationship for the aromatic/heteroaromatic N-methylethylenediamine inhibitors of PRMT1 and review current progress of PRMT1 inhibitors in clinical trials.

中文翻译：

蛋白精氨酸甲基转移酶 1 的小分子和肽抑制剂的结构、功能和活性

蛋白精氨酸 N-甲基转移酶（PRMT）是 S-腺苷-l-蛋氨酸（SAM）依赖性酶家族，可将甲基转移到蛋白质中精氨酸残基的 ω-N 上。PRMT 参与调节基因表达、RNA 剪接和其他活动。PRMT1 负责大多数细胞精氨酸甲基化，其失调与许多癌症有关。因此，许多小组使用小分子和肽抑制剂靶向 PRMT1。在这个观点中，我们讨论了 PRMT1 的选定肽和小分子抑制剂的结构和功能。我们检查了靶向底物精氨酸肽、SAM 或两者结合位点的抑制剂，以及产生的抑制类型。将讨论小分子和双底物肽，和/或 PRMT 过渡态模拟抑制剂以及烷基化 PRMT 的抑制剂。我们定义了 PRMT1 的芳香族/杂芳香族 N-甲基乙二胺抑制剂的结构-活性关系，并回顾了 PRMT1 抑制剂在临床试验中的当前进展。

更新日期：2024-09-09

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