PRMT5 inhibition by SCR-6920 downregulates HIF-1α and exhibits synergistic antitumor activity with bevacizumab in ovarian cancer

Protein arginine methyltransferase 5 (PRMT5) is a critical therapeutic target in cancer. Here, we report SCR-6920, a potent and selective oral PRMT5 inhibitor characterized by a substrate-competitive binding mode to PRMT5:MEP50 with high affinity. SCR-6920 shows broad anti-tumor activity in vitro and in vivo, along with favorable pharmacokinetics and tumor-biased distribution. Notably, RNAseq 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 enhanced hypoxia-induced pathway disruption, and further in vivo efficacy study demonstrated 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.