2. Academic Validation
  3. Discovery of novel indazole derivatives as type Ⅰ PRMTs inhibitors for the treatment of triple-negative breast cancer

Discovery of novel indazole derivatives as type Ⅰ PRMTs inhibitors for the treatment of triple-negative breast cancer

  • Eur J Med Chem. 2025 Dec 15:300:118123. doi: 10.1016/j.ejmech.2025.118123.
Qiangsheng Zhang 1,  Shuyan Zhou 2,  Xueying Chen 3,  Luoting Yu 4,  Xianli Zhou 5
Affiliations

Affiliations

  • 1 School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, PR China.
  • 2 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Children's Medicine Key Laboratory of Sichuan Province, Sichuan University, and Collaborative Innovation Center for Biotherapy, 17#3rd Section, Ren Min South Road, Chengdu, 610041, PR China.
  • 3 School of Basic Medical Sciences, Guilin Medical University, Guilin, 541199, PR China.
  • 4 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Children's Medicine Key Laboratory of Sichuan Province, Sichuan University, and Collaborative Innovation Center for Biotherapy, 17#3rd Section, Ren Min South Road, Chengdu, 610041, PR China. Electronic address: yuluot@scu.edu.cn.
  • 5 School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, PR China; Yibin Institute of Southwest Jiaotong University, Yibin, Sichuan, PR China. Electronic address: zhouxl@swjtu.edu.cn.
PMID: 40929806 DOI: 10.1016/j.ejmech.2025.118123
Abstract

Type I protein arginine methyltransferases (PRMTs) play significant roles in various diseases, including Cancer. The inhibition of type I PRMTs significantly suppresses the growth of breast Cancer, particularly triple-negative breast Cancer (TNBC). The development of potent and selective type I PRMTs inhibitors has become a research hotspot in recent years. In this study, a series of six-membered fused five-membered heterocyclic derivatives were designed via a scaffold hopping strategy. Through structural optimization, the pyrazole derivative B9, namely SKLB06329, was obtained. This compound exhibited inhibitory activity against Type I PRMTs at the nanomolar to low nanomolar level and showed good selectivity for PRMT5/7 and various lysine methyltransferases. SKLB06329 could significantly inhibit the proliferation of TNBC cells, induce Apoptosis, and suppress the expression of asymmetric dimethylarginine (ADMA) within cells. When administered intravenously, it demonstrated favorable pharmacokinetic properties. SKLB06329 can serve as an effective lead compound for further research, providing a new strategy for the treatment of TNBC.

Keywords

Histone methylation; Selectivity; TNBC; Type Ⅰ PRMTs.

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