Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes the formation of symmetric dimethylarginine in a number of nuclear and cytoplasmic proteins. Although the cellular functions of PRMT5 have not been fully unraveled, it has been implicated in a number of cellular processes like RNA processing, signal transduction, and transcriptional regulation. PRMT5 is ubiquitously expressed in most tissues and its expression has been shown to be elevated in several cancers including breast cancer, gastric cancer, glioblastoma, and lymphoma. Here, we describe the identification and characterization of a novel and selective PRMT5 inhibitor with potent in vitro and in vivo activity. Compound 1 (also called LLY-283) inhibited PRMT5 enzymatic activity in vitro and in cells with IC₅₀ of 22 ± 3 and 25 ± 1 nM, respectively, while its diastereomer, compound 2 (also called LLY-284), was much less active. Compound 1 also showed antitumor activity in mouse xenografts when dosed orally and can serve as an excellent probe molecule for understanding the biological function of PRMT5 in normal and cancer cells.

中文翻译：

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LLY-283，精氨酸甲基转移酶5，PRMT5的强效和选择性抑制剂，具有抗肿瘤活性

蛋白质精氨酸甲基转移酶5（PRMT5）是II型精氨酸甲基转移酶，可催化许多核蛋白和细胞质蛋白中对称的二甲基精氨酸的形成。尽管PRMT5的细胞功能尚未完全阐明，但已涉及许多细胞过程，如RNA加工，信号转导和转录调控。PRMT5在大多数组织中普遍表达，并且它的表达在几种癌症（包括乳腺癌，胃癌，胶质母细胞瘤和淋巴瘤）中表达升高。在这里，我们描述了具有有效的体外和体内活性的新型和选择性PRMT5抑制剂的鉴定和表征。化合物1（也称为LLY-283）在体外和细胞中抑制PRMT5的酶活性，IC _50分别为22±3和25±1 nM，而其非对映体化合物2（也称为LLY-284）的活性低得多。口服给药时，化合物1在小鼠异种移植物中也显示出抗肿瘤活性，并且可以用作了解PRMT5在正常细胞和癌细胞中的生物学功能的出色探针分子。