Xingxing Cheng, Zheqi Hu, Huihuan Mao, Ziyue Li, Zhen Wang, Yixuan Tang, Shihui Huang, Yujing Huang, Chunxiang Yin, Hanxi Xing, Sijia Chen, Yuhan Jiang, Ting Hu, Jiawen Zuo, Wenxin Yan, Hongfeng Gu, Ping Wei, Yungen Xu, Qihua Zhu, Yi Zou
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 IC 50 = 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.