Discovery of First-in-Class Protein Arginine Methyltransferase 5 (PRMT5) Degraders

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 15 (MS4322). Here, we report the design, synthesis, and characterization of compound 15 and two structurally similar controls 17 (MS4370) and 21 (MS4369), with impaired binding to the von Hippel-Lindau E3 ligase and PRMT5, respectively. Compound 15, but not 17 and 21, effectively reduced the PRMT5 protein level in MCF-7 cells. Our mechanism studies indicate that compound 15 degraded PRMT5 in an E3 ligase- and proteasome-dependent manner. Compound 15 also effectively reduced the PRMT5 protein level and inhibited growth in multiple cancer cell lines. Moreover, compound 15 was highly selective for PRMT5 in a global proteomic study and exhibited good plasma exposure in mice. Collectively, compound 15 and its two controls 17 and 21 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（protein arginine methyltransferase 5, PRMT5）的异常表达与多种癌症密切相关。本研究借助蛋白水解靶向嵌合（proteolysis targeting chimera）技术，发现了首款PRMT5降解剂15（MS4322）。本文报道了化合物15以及两种结构相似的对照化合物17（MS4370）和21（MS4369）的设计、合成与表征；其中对照化合物17和21分别对希佩尔-林道E3泛素连接酶（von Hippel-Lindau E3 ligase）和PRMT5的结合能力受损。实验结果显示，仅化合物15可有效降低MCF-7细胞中PRMT5的蛋白水平，而非17和21。机制研究表明，化合物15以依赖E3泛素连接酶和蛋白酶体的方式降解PRMT5。此外，化合物15可有效降低多种癌细胞系中的PRMT5蛋白水平并抑制细胞增殖。在全局蛋白质组学研究中，化合物15对PRMT5展现出极高的选择性，且在小鼠体内具有良好的血浆暴露量。综上，化合物15及其两种对照化合物17、21是探究PRMT5在健康与疾病状态下功能的极具价值的化学工具。