Discovery and Mechanism of 16-19F, a Novel Synthetic Lethal Inhibitor of the PRMT5•MTA Complex in MTAP-Deleted Cancer Cells.

IF 3.5 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

ACS Chemical Biology Pub Date : 2025-05-29 DOI:10.1021/acschembio.5c00160

Zhihang Shen, Xiaozhi Yang, Gustavo Seabra, Xueyong Xu, Jiawei Dong, Jason Orr Brant, Wei Zhou, Juan Guan, Wen Jiang, Chenglong Li

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引用次数: 0

Abstract

Protein arginine methyltransferase 5 (PRMT5), which uniquely binds to 5'-methylthioadenosine (MTA) among the PRMT family, is emerging as an attractive epigenetic target for 5'-methylthioadenosine phosphorylase (MTAP)-deleted cancer treatments. Here, we report the discovery of a novel inhibitor 16-19F, which is a potent binder to the PRMT5•MTA, PRMT5•SAH, and PRMT5•SAM complexes and selectively inhibited MTAP-deleted cancer cell growth. Based on transcriptome analysis, we found that kinetochore metaphase signaling and cell cycle control of the chromosomal replication pathway were downregulated after 16-19F treatment in the MDA-MB-231 TNBC cell line. Additionally, we identified a new PRMT5 substrate, MCM7, an important component of DNA helicase, and figured out the potential methylation site Arg219 by site-directed mutagenesis and computational analysis. Moreover, we showed that 16-19F treatment regulated MCM7 localization, which is involved through liquid-liquid phase separation mechanisms, including the formation of stress granules. Together, we discovered a potential novel drug candidate and revealed an unknown mechanism in which PRMT5 methylation altered MCM7 localization by modulating stress granule formation.

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mtap缺失癌细胞中PRMT5•MTA复合物的新型合成致死抑制剂16-19F的发现及其机制

蛋白精氨酸甲基转移酶5 （PRMT5）是PRMT家族中唯一结合5'-甲基硫代腺苷（MTA）的蛋白，它正在成为5'-甲基硫代腺苷磷酸化酶（MTAP）缺失的癌症治疗的一个有吸引力的表观遗传靶点。在这里，我们报告了一种新的抑制剂16-19F的发现，它是PRMT5•MTA， PRMT5•SAH和PRMT5•SAM复合物的有效结合物，并选择性地抑制mtap缺失的癌细胞生长。通过转录组分析，我们发现在MDA-MB-231 TNBC细胞系中，16-19F处理后，着丝粒中期信号和染色体复制途径的细胞周期调控下调。此外，我们发现了一个新的PRMT5底物MCM7，这是DNA解旋酶的一个重要组成部分，并通过位点定向突变和计算分析找到了潜在的甲基化位点Arg219。此外，我们发现16-19F处理调节MCM7的定位，这是通过液-液相分离机制参与的，包括应力颗粒的形成。我们共同发现了一种潜在的新型候选药物，并揭示了PRMT5甲基化通过调节应激颗粒形成改变MCM7定位的未知机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Chemical Biology 生物-生化与分子生物学

CiteScore

7.50

自引率

5.00%

发文量

353

审稿时长

3.3 months

期刊介绍： ACS Chemical Biology provides an international forum for the rapid communication of research that broadly embraces the interface between chemistry and biology. The journal also serves as a forum to facilitate the communication between biologists and chemists that will translate into new research opportunities and discoveries. Results will be published in which molecular reasoning has been used to probe questions through in vitro investigations, cell biological methods, or organismic studies. We welcome mechanistic studies on proteins, nucleic acids, sugars, lipids, and nonbiological polymers. The journal serves a large scientific community, exploring cellular function from both chemical and biological perspectives. It is understood that submitted work is based upon original results and has not been published previously.