Discovery of novel cereblon-recruiting PRMT5 degraders with in vivo efficacy against triple-negative breast cancer

  • Eur J Med Chem. 2026 Nov 15:318:119199. doi: 10.1016/j.ejmech.2026.119199.
Yuzhan Li  1 ,  Yaxun Guo  2 ,  Dazhao Mi  1 ,  Fubing Li  3 ,  Jingfeng Song  4 ,  Qiansen Zhang  5 ,  Ceshi Chen  6 ,  Zhigang Yu  7 ,  Yihua Chen  8
Affiliations
  • 1. Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200241, China.
  • 2. Breast Center, The Second Qilu Hospital of Shandong University, Shandong University, Jinan, 250033, China.
  • 3. Yunnan Key Laboratory of Breast Cancer Precision Medicine, Academy of Biomedical Engineering, Kunming Medical University, Kunming, 650500, China.
  • 4. School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products and Yunnan College of Modern Biomedical Industry, Kunming Medical University, Kunming, Yunnan, 650500, China; Yunnan Key Laboratory of Breast Cancer Precision Medicine, Academy of Biomedical Engineering, Kunming Medical University, Kunming, 650500, China.
  • 5. Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200241, China. Electronic address: [email protected].
  • 6. Yunnan Key Laboratory of Breast Cancer Precision Medicine, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, 650118, China; Yunnan Key Laboratory of Breast Cancer Precision Medicine, Academy of Biomedical Engineering, Kunming Medical University, Kunming, 650500, China. Electronic address: [email protected].
  • 7. Breast Center, The Second Qilu Hospital of Shandong University, Shandong University, Jinan, 250033, China; Shandong Key Laboratory of Cancer Digital Medicine, Jinan, 250033, China; Shandong Provincial Engineering Laboratory of Translational Research on Prevention and Treatment of Breast Disease, Jinan, 250033, China; Institute of Translational Medicine of Breast Disease Prevention and Treatment, Shandong University, Jinan, 250033, China. Electronic address: [email protected].
  • 8. Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200241, China; School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products and Yunnan College of Modern Biomedical Industry, Kunming Medical University, Kunming, Yunnan, 650500, China. Electronic address: [email protected].
PMID: 42566881 DOI: 10.1016/j.ejmech.2026.119199
Abstract

The epigenetic regulator protein arginine methyltransferase 5 (PRMT5) is aberrantly overexpressed in Triple-Negative Breast Cancer (TNBC) and represents a promising therapeutic target. Currently reported PRMT5-targeting PROTAC degraders (MS4322 and MS115) are both derived from a tetrahydroisoquinoline scaffold. These compounds require treatment for more than five days to exert effective antiproliferative activities, and no in vivo antitumor efficacy has been reported. To address these limitations, we adopted the carbazole-based PRMT5 Inhibitor PJ-68, which features a lower molecular weight and a more accessible linker attachment site. Herein, we reported a series of novel PRMT5 degraders with carbazole scaffold. The representative compound YZ-17 degraded PRMT5 (DC50 = 2.2 μM in HCC1806 and 3.3 μM in HCC1937 cells) and its adaptor protein MEP50 (DC50 = 2.0 μM and 2.9 μM, respectively) within 24 h. YZ-17 also suppressed PRMT5-mediated symmetric dimethylarginine (sDMA) modification and colony formation, induced G1 phase cell cycle arrest, and displayed favorable antiproliferative activities across several TNBC cell lines (IC50 = 2.6 - 3.7 μM). Importantly, YZ-17 showed in vivo efficacy in an HCC1806 xenograft model, achieving a tumor growth inhibition (TGI) of 44.12% at 30 mg/kg (i.p., every other day) without obvious toxicity. Collectively, YZ-17 represents a structurally novel PRMT5 Degrader with rapid onset of action, effective in vitro and in vivo anti-TNBC activity, offering a distinct chemical tool for further functional studies of PRMT5.

Keywords
CRBN; Carbazole; PRMT5; PROTACs; TNBC.
Products