Discovery of Oxime Ether Derivatives as Second-Generation PRMT5 Inhibitors for the Treatment of Triple Negative Breast Cancer.

PRMT5 is frequently overexpressed in various human malignancies. The second-generation PRMT5 inhibitors targeting MTAP-deleted cancers exhibit excellent selectivity against MTAP-wild-type cell lines, offering the potential to minimize off-target effects and enhance therapeutic efficacy. Recent studies have demonstrated that triple-negative breast cancer (TNBC) is more prevalent in cases with MTAP loss, suggesting that this approach may provide a promising therapeutic strategy for TNBC. In this study, we present a novel series of oxime ether derivatives that function as second-generation PRMT5 inhibitors. The representative compound I-14 exhibited potent inhibitory activity in both biochemical and cellular assays (PRMT5·MTA IC50 = 4.4 nM), and displayed high cellular selectivity (>1000-fold) between MTAP-null and MTAP-WT HCT116 cells. Furthermore, I-14 displayed acceptable pharmacokinetic properties and significant antitumor efficacy (TGI = 84.8% at 100 mg/kg) in an MTAP-null MDA-MB-231 xenograft model. Our findings suggest that I-14 is a promising lead compound for MTAP-null TNBC treatment.