Development of a Selective and Potent PRMT4 PROTAC Degrader with Efficacy against Multiple Myeloma in Vitro and in Vivo

Protein arginine methyltransferase 4 (PRMT4) is highly expressed in relapsed or refractory multiple myeloma (MM) and is associated with poor prognosis. Conventional PRMT4 inhibitors face challenges including inadequate efficacy, acquired resistance, and inability to inhibit nonenzymatic functions. In this study, we developed a proteolysis targeting chimera (PROTAC) targeting PRMT4, named C199, which is composed of the PRMT4 inhibitor EZM2302, a linker, and a von Hippel-Lindau (VHL) E3 ligase ligand. C199 demonstrated potent cellular degradation (DC50 = 106 nM, Dmax = 93.1%) and showed high selectivity for PRMT4 over other protein arginine methyltransferases. Importantly, in vivo studies showed that C199 had a relatively long half-life (10.10 h versus 4.89 h for EZM2302) and demonstrated strong antitumor activity (TGI = 78% versus 49% for EZM2302) without significant toxicity even at high doses. These findings provide the first evidence that PRMT4-targeted PROTAC degrader can exhibit therapeutic effects in vivo, offering a promising new therapeutic strategy for MM.