PRMT5 inhibitor SCR-6920 downregulates HIF-1alpha and exhibits synergistic antitumor activity with Bevacizumab

PRMT5 has emerged as a promising epigenetic target for cancer therapy, yet its potential in rational combination strategies remains inadequately explored. This study aims to characterize the novel, oral PRMT5 inhibitor SCR-6920, with a particular focus on its ability to synergize with anti-angiogenic therapy by modulating the hypoxia-inducible factor-1alpha (HIF-1alpha)/vascular endothelial growth factor (VEGF) axis. SCR-6920 is a potent and highly selective PRMT5 inhibitor that has undergone extensive preclinical evaluation and is currently in phase 1 clinical trials (NCT05528055). It demonstrated broad antitumor efficacy across a panel of cancer cell lines in vitro and in xenograft models in vivo . A key finding from RNA-seq analysis was that PRMT5 inhibition by SCR-6920 led to the downregulation of angiogenesis pathways, particularly those involving VEGF. Subsequent mechanistic studies revealed that SCR-6920 significantly reduced hypoxia-induced HIF-1alpha protein levels without altering its mRNA expression. This effect was mediated by promoting the ubiquitination and subsequent proteasomal degradation of the HIF-1alpha protein. Consequently, SCR-6920 treatment resulted in the decreased expression and secretion of VEGF, a major downstream target of HIF-1alpha. Based on this mechanism targeting the HIF-1alpha/VEGF axis, we investigated and demonstrated a robust synergistic antitumor effect between SCR-6920 and the anti-VEGF antibody bevacizumab in an ovarian cancer xenograft model. This combination resulted in significantly enhanced tumor growth suppression without an increase in toxicity, providing a strong mechanistic rationale for this combination strategy. Furthermore, SCR-6920 exhibited synergistic or additive effects when combined with several standard-of-care chemotherapies and targeted agents for solid tumors, including paclitaxel, docetaxel, doxorubicin, and olaparib. In summary, our work identifies SCR-6920 as a promising clinical-stage PRMT5 inhibitor with a unique ability to destabilize HIF-1alpha and suppress VEGF signaling. The unveiled mechanism, whereby PRMT5 inhibition promotes HIF-1alpha degradation, provides the foundation for the observed synergistic activity with bevacizumab. These findings position SCR-6920 as a compelling clinical candidate for solid tumors, particularly in rational combinations aimed at overcoming resistance to anti-angiogenic therapy.