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

  • J Med Chem. 2026 Feb 12;69(3):2647-2665. doi: 10.1021/acs.jmedchem.5c02570.
Xingxing Cheng  1  2 ,  Zheqi Hu  1  2  3 ,  Huihuan Mao  1  2  3 ,  Ziyue Li  1  2  3 ,  Zhen Wang  1  2  3 ,  Yixuan Tang  1  2  3 ,  Shihui Huang  1  2  3 ,  Yujing Huang  1  2  3 ,  Chunxiang Yin  1  2 ,  Hanxi Xing  2 ,  Sijia Chen  2 ,  Yuhan Jiang  2 ,  Ting Hu  2 ,  Jiawen Zuo  2 ,  Wenxin Yan  1  2  3 ,  Hongfeng Gu  2  3 ,  Ping Wei  4 ,  Yungen Xu  1  2  3 ,  Qihua Zhu  1  2 ,  Yi Zou  2  3
Affiliations
  • 1. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China.
  • 2. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • 3. Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China.
  • 4. Hefei Institute of Pharmaceutical Industry Co. Ltd., Hefei 230601, China.
PMID: 41527338 DOI: 10.1021/acs.jmedchem.5c02570
Abstract

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.

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