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

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

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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