PRMT5 Inhibition by SCR-6920 Downregulates HIF-1α and Exhibits Synergistic Antitumor Activity with Bevacizumab in...

Protein arginine methyltransferase 5 (PRMT5) is a critical therapeutic target in cancer. In this study, we report SCR-6920, a potent and selective oral PRMT5 inhibitor characterized by a substrate-competitive binding mode to PRMT5:methylosome protein 50 with high affinity. SCR-6920 shows broad antitumor activity in vitro and in vivo, along with favorable pharmacokinetics and tumor-biased distribution. Notably, RNA sequencing analysis links vascular endothelial growth factor (VEGF) to PRMT5, and further studies show that SCR-6920 downregulates hypoxia-inducible factor-1α (HIF-1α) through the ubiquitin-proteasome degradation pathway, thereby reducing downstream VEGF expression and secretion. Thus, PRMT5 inhibition enhances hypoxia-induced pathway disruption, and a further in vivo efficacy study demonstrates a synergistic effect for SCR-6920 combined with bevacizumab against ovarian cancer. Additionally, SCR-6920 improves the efficacy of clinical first-line ovarian cancer therapies (paclitaxel, docetaxel, doxorubicin, and olaparib). This study identifies a promising PRMT5 inhibitor with synergistic activity with bevacizumab and reveals its regulation of HIF-1α signaling, highlighting the therapeutic potential of PRMT5 inhibition in combination regimens for ovarian cancer.