2. Academic Validation
  3. Discovery of a potent and orally bioavailable type Ⅰ PRMTs inhibitor for triple-negative breast cancer treatment

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

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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