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

Abstract

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 <b>15</b> (MS4322). Here, we report the design, synthesis, and characterization of compound <b>15</b> and two structurally similar controls <b>17</b> (MS4370) and <b>21</b> (MS4369), with impaired binding to the von Hippel-Lindau E3 ligase and PRMT5, respectively. Compound <b>15</b>, but not <b>17</b> and <b>21</b>, effectively reduced the PRMT5 protein level in MCF-7 cells. Our mechanism studies indicate that compound <b>15</b> degraded PRMT5 in an E3 ligase- and proteasome-dependent manner. Compound <b>15</b> also effectively reduced the PRMT5 protein level and inhibited growth in multiple cancer cell lines. Moreover, compound <b>15</b> was highly selective for PRMT5 in a global proteomic study and exhibited good plasma exposure in mice. Collectively, compound <b>15</b> and its two controls <b>17</b> and <b>21</b> are valuable chemical tools for exploring the PRMT5 functions in health and disease.