Discovery of a potent and orally bioavailable type Ⅰ PRMTs inhibitor for triple-negative breast cancer treatment

  • Acta Pharmacol Sin. 2026 Jan 16. doi: 10.1038/s41401-025-01713-5.
Shu-Yan Zhou  #  1 ,  Qiang-Sheng Zhang  #  2 ,  Lu Li  3 ,  Zhi-Hao Liu  4 ,  Xiang Hu  1 ,  Xue-Ying Chen  5 ,  Xiao Li  1 ,  Zhan-Zhan Feng  1 ,  Guo-Quan Wan  1 ,  Luo-Ting Yu  6  7
Affiliations
  • 1. Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 2. School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China.
  • 3. Department of Pharmacy, NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Clinical Trial Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 4. Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 5. School of Basic Medical Sciences, Guilin Medical University, Guilin, 541199, China.
  • 6. Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. [email protected].
  • 7. Children's Medicine Key Laboratory of Sichuan Province, Sichuan University, Chengdu, 610041, China. [email protected].
  • # Contributed equally.
PMID: 41545753 DOI: 10.1038/s41401-025-01713-5
Abstract

Triple-negative breast Cancer (TNBC) remains the most refractory breast Cancer subtype because of its high invasiveness, lack of therapeutic targets and heterogeneity. Type I protein arginine methyltransferases (PRMTs) are important epigenetic Enzymes that catalyze the methylation of arginine residues in various proteins, playing crucial roles in numerous cellular processes. Targeting type I PRMTs represents a promising strategy for TNBC. In this study we characterized a novel selective type I PRMTs inhibitor, SKLB06489. Compared with the precursor compound SKLB06329 (F = 0.2%), SKLB06489 exhibited a markedly enhanced oral bioavailability (F = 88.4%). SKLB06489 inhibited PRMT1, PRMT6, and PRMT8 with IC50 values of 64.55, 4.21, and 51.27 nM, respectively. In TNBC cell lines MDA-MB-231, Hs578T, and BT549, SKLB06489 dose-dependently inhibited cell proliferation and colony formation with IC50 values in the low micromolar range. In MDA-MB-231 subcutaneous xenograft models, administration of SKLB06489 (40, 80 mg·kg-1·d-1, i.g. for 33 days) dose-dependently suppressed tumor growth. RNA Sequencing and in vitro validation revealed that SKLB06489 inhibited TNBC proliferation by impairing DNA replication, compromising DNA damage repair, and ultimately inducing G0/G1-phase cell cycle arrest and Apoptosis. In addition, SKLB06489 (5, 10 μΜ) dose-dependently enhanced intracellular Cholesterol efflux in MDA-MB-231 cells and Hs578T cells via upregulation of the ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1), thereby disrupting Cholesterol metabolic homeostasis. We conclude that SKLB06489 is a potent type Ⅰ PRMTs inhibitor with great therapeutic potential and is expected to overcome the TNBC treatment bottleneck. The discovery of SKLB06489-regulated Cholesterol homeostasis provides a novel perspective on the biological function of type Ⅰ PRMTs, particularly their role in regulating metabolic pathway.

Keywords
ABCA1; ABCG1; TNBC; antitumor activity; cholesterol efflux; type Ⅰ PRMTs.
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