2. Academic Validation
  3. Design and synthesis of novel styrylquinolinium derivatives for the treatment of breast Cancer: Targeting the c-Myc G-quadruplex

Design and synthesis of novel styrylquinolinium derivatives for the treatment of breast Cancer: Targeting the c-Myc G-quadruplex

  • Eur J Med Chem. 2025 Jul 5:291:117663. doi: 10.1016/j.ejmech.2025.117663.
Xutong Wang 1,  Yu Liu 1,  Zeyu Gao 1,  Xiaodong Fang 1,  Kejing Ma 1,  Meng Sun 1,  Qiming Li 1,  Bing Wang 1,  Yong Zhang 2,  Xin Zhao 3,  Weina Han 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, HarBin Medical University, Harbin, 150081, China.
  • 2 Department of Pharmacology, State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD, State Key Laboratory -Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China; State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), College of Pharmacy, and Department of Cardiology, The Second Affiliated Hospital, Harbin Medical University, Harbin, 150081, China; Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin, 150081, China. Electronic address: hmuzhangyong@hotmail.com.
  • 3 Department of Pharmacology, State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD, State Key Laboratory -Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China. Electronic address: zhaoxin@hrbmu.edu.cn.
  • 4 Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, HarBin Medical University, Harbin, 150081, China. Electronic address: hanweina@hrbmu.edu.cn.
PMID: 40262296 DOI: 10.1016/j.ejmech.2025.117663
Abstract

Inhibiting c-Myc gene expression by targeting the c-Myc G-quadruplex (G4) represents an effective strategy for breast Cancer treatment. In order to find ligands that can specifically target the c-Myc G4, we utilized styrylquinolinium as the core element to anchor G4, and proposed three guiding principles for the design and synthesis of G4 ligands. Finally, compound W11 was identified as the compound skeleton which has the potential to target c-Myc G4. On this basis, compound X3 with higher c-Myc G4 selectivity was developed. Both W11 and X3 demonstrate significant inhibitory effects on breast Cancer. Subsequently, we used molecular docking and molecular dynamics simulation to analyze the relationship between the targeting ability and chemical structure of W11 derivatives, and proposed a detailed structure-activity relationship model. Additionally, we found that the free energy landscape (FEL) of ligands with high selectivity and affinity for G4 is "centralized and singular" during this process. Cell experiments and MCF-7 tumor xenograft experiments demonstrated that W11 inhibited the proliferation and metastasis of breast Cancer cells by downregulating the transcription and translation of the c-Myc gene. Moreover W11 significantly inhibited tumor tissue growth in vivo without causing obvious damage to major organs.

Keywords

Breast cancer; Drug synthesis; G - quadruplex; c-Myc.

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