Overview of PRMT1 modulators: Inhibitors and degraders

Protein arginine methyltransferase 1 (PRMT1) is pivotal in executing normal cellular functions through its catalytic action on the methylation of arginine side chains on protein substrates. Emerging research has revealed a correlation between the dysregulation of PRMT1 expression and the initiation and progression of tumors, significantly influence on patient prognostication, attributed to the essential role played by PRMT1 in a number of biological processes, including transcriptional regulation, signal transduction or DNA repair. Therefore, PRMT1 emerged as a promising therapeutic target for anticancer drug discovery in the past decade. In this review, we first summarize the structure and biological functions of PRMT1 and its association with cancer. Next, we focus on the recent advances in the design and development of PRMT1 modulators, including isoform-selective PRMT1 inhibitors, pan type I PRMT inhibitors, PRMT1-based dual-target inhibitors, and PRMT1-targeting PROTAC degraders, from the perspectives of rational design, pharmacodynamics, pharmacokinetics, and clinical status. Finally, we discuss the challenges and future directions for PRMT1-based drug discovery for cancer therapy.