发现首例靶向蛋白质精氨酸甲基转移酶 5（PRMT5）的降解剂。
Discovery of First-in-Class Protein Arginine Methyltransferase 5 (PRMT5) Degraders.
机构信息
Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas 78957, United States.
出版信息
J Med Chem. 2020 Sep 10;63(17):9977-9989. doi: 10.1021/acs.jmedchem.0c01111. Epub 2020 Aug 21.
The aberrant expression of protein arginine methyltransferase 5 (PRMT5) has been associated with multiple cancers. Using the proteolysis targeting chimera technology, we discovered a first-in-class PRMT5 degrader (MS4322). Here, we report the design, synthesis, and characterization of compound and two structurally similar controls (MS4370) and (MS4369), with impaired binding to the von Hippel-Lindau E3 ligase and PRMT5, respectively. Compound , but not and , effectively reduced the PRMT5 protein level in MCF-7 cells. Our mechanism studies indicate that compound degraded PRMT5 in an E3 ligase- and proteasome-dependent manner. Compound also effectively reduced the PRMT5 protein level and inhibited growth in multiple cancer cell lines. Moreover, compound was highly selective for PRMT5 in a global proteomic study and exhibited good plasma exposure in mice. Collectively, compound and its two controls and are valuable chemical tools for exploring the PRMT5 functions in health and disease.
蛋白质精氨酸甲基转移酶 5（PRMT5）的异常表达与多种癌症有关。本研究采用蛋白酶靶向嵌合体技术，发现了一种首创的 PRMT5 降解剂（MS4322）。本研究报告了化合物的设计、合成和表征，以及两种结构相似的对照物（MS4370）和（MS4369）的设计、合成和表征，它们分别与 von Hippel-Lindau E3 连接酶和 PRMT5 的结合受损。与对照物和 相比，化合物 可有效降低 MCF-7 细胞中的 PRMT5 蛋白水平。本研究的机制研究表明，化合物 以 E3 连接酶和蛋白酶体依赖的方式降解 PRMT5。化合物 还可有效降低多种癌细胞系中的 PRMT5 蛋白水平并抑制其生长。此外，在全蛋白质组学研究中，化合物 对 PRMT5 具有高度选择性，并在小鼠体内表现出良好的血浆暴露。综上所述，化合物 和其两种对照物 和 是探索 PRMT5 在健康和疾病中的功能的有价值的化学工具。
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