PRMT5 inhibition by SCR-6920 leads to downregulation of HIF-1α and exhibits synergistic antitumor activity with bevacizumab in ovarian cancer

Protein arginine methyltransferase 5 (PRMT5) is a desirable anticancer target due to its extensive involvement in cellular processes associated with tumor initiation and progression. This study describes an oral PRMT5 selective inhibitor, SCR-6920, with potent inhibitory activity against multiple tumor types. Cryo-EM structure shows that SCR-6920 binds to PRMT5:MEP50 in a substrate-competitive mode with high binding affinity. 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) expression through the ubiquitin-proteasome degradation pathway, thereby reducing downstream VEGF secretion. 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). SCR-6920 has progressed into phase 1 clinical trials for solid tumors, and this study paves the way for its future clinical combination exploration in ovarian cancer. To determine the oncogenic properties of PRMT5, we performed RNA sequence analysis on A2780 cells that were treated with either DMSO or SCR-6920 for 48 hours.