Discovery of PRMT3 Degrader for the Treatment of Acute Leukemia

Abstract

Protein arginine methyltransferase 3 (PRMT3) has emerged as a key regulator of gene expression and is implicated in various essential cellular processes, making it a promising therapeutic target, particularly in the context of human cancers. Despite the development of several PRMT3 inhibitors designed to block its enzymatic activity, these efforts have yielded limited success in eliminating the accumulation of PRMT3-mediated ω-NG,NG-asymmetric dimethylarginine (ADMA) within cells. Furthermore, the non-catalytic, or non-enzymatic, roles of PRMT3 remain poorly understood and warrant further investigation.

In this study, the creation and characterization of a novel class of MDM2-recruiting proteolysis targeting chimeras (PROTACs) specifically engineered to degrade PRMT3 are described. Among them, compound 11 represents a first-in-class degrader that effectively diminishes both PRMT3 protein levels and intracellular ADMA deposition. Notably, compound 11 exhibits potent anti-leukemic activity, significantly inhibiting the proliferation of acute leukemia cells. Its antiproliferative effect surpasses that of SGC707, a conventional PRMT3 enzymatic inhibitor, suggesting a superior mechanism of action.

Detailed mechanistic analyses reveal that compound 11 induces widespread transcriptional alterations within leukemia cells. These changes are characterized by the activation of intrinsic apoptotic pathways and endoplasmic reticulum (ER) stress responses, along with the suppression of gene networks governed by E2F and MYC transcription factors, as well as pathways associated with oxidative phosphorylation. This multifaceted impact on cellular signaling highlights the compound’s broad biological activity beyond enzymatic inhibition alone.

Furthermore, when used in combination with the glycolysis inhibitor 2-deoxy-D-glucose (2-DG), compound 11 demonstrates a synergistic effect in halting cell growth. This combination treatment markedly reduces ATP levels and enhances the induction of intrinsic apoptosis, reinforcing the therapeutic promise of targeted PRMT3 degradation as a novel strategy for cancer treatment.

Altogether, these findings underscore the significance of compound 11 as a powerful chemical probe for dissecting both the enzymatic and non-enzymatic roles of PRMT3. They also establish a strong foundation for the future development of targeted PRMT3 degraders as potential therapeutic agents in oncology.