2. Academic Validation
  3. Design and synthesis of Riluzole-Ciprofloxacin hybrids as selective MST3 inhibitors for cancer treatment

Design and synthesis of Riluzole-Ciprofloxacin hybrids as selective MST3 inhibitors for cancer treatment

  • Eur J Med Chem. 2025 Jun 28:297:117923. doi: 10.1016/j.ejmech.2025.117923.
Deping Li 1,  Shuoqi Huang 2,  Jinjin Lai 3,  Jianxiong Yang 4,  Wenwu Liu 5,  Renze Yang 6
Affiliations

Affiliations

  • 1 Department of Pharmacy, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, People's Republic of China; Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Gannan Medical University), Ministry of Education, People's Republic of China; Jiangxi Provincial Key Laboratory of Tissue Engineering (Gannan Medical University), People's Republic of China.
  • 2 Pharmacy Department, Tianjin Hospital, Tianjin, 300210, People's Republic of China.
  • 3 Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Gannan Medical University), Ministry of Education, People's Republic of China; Jiangxi Provincial Key Laboratory of Tissue Engineering (Gannan Medical University), People's Republic of China; College of Pharmacy, Gannan Medical University, Ganzhou, 314000, People's Republic of China.
  • 4 The First Clinical College, Gannan Medical University, Ganzhou, 341000, People's Republic of China.
  • 5 Department of Pharmacy, Peking University First Hospital, Beijing, 100034, People's Republic of China. Electronic address: sunny961010@163.com.
  • 6 Department of Pharmacy, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, People's Republic of China. Electronic address: zerenyang@163.com.
PMID: 40609223 DOI: 10.1016/j.ejmech.2025.117923
Abstract

The MST3 isozyme is integral to the modulation of cellular proliferation and Apoptosis, with its dysregulation critically implicated in the tumorigenesis of high-grade neoplasms. Current investigations into MST3 inhibitors are in their initial stages, characterized by restricted structural diversity and suboptimal selectivity. Previous studies have shown that Riluzole and Ciprofloxacin have the potential to be repurposing into the tumor field. Notably, their hybridization may facilitate the formation of a continuous hydrogen bonding network between donor and acceptor moieties, thereby augmenting their applicability as novel kinase inhibitors. In this study, we designed and synthesized a series of Riluzole-Ciprofloxacin hybrids, subsequently identifying the lead compound LD-1 (GI50 = 683.1 nM in HepG2 cells) through an anti-proliferative screening process. Comprehensive kinase profiling and target inhibition assays revealed that LD-1 functions as a potent and selective inhibitor of MST3, exhibiting an IC50 value of 122.4 nM. Preliminary mechanistic studies indicated that LD-1 reduced the expression levels of cleaved Caspase-3 and Bcl-2, resulted in inducing HepG2 cells Apoptosis. Meanwhile, it decreased the expression level of cyclin B1 in a concentration-dependent manner, leading to cell cycle at the G2/M transition. The in vivo experiments demonstrated that LD-1 significantly suppressed tumor growth (TGI = 47.64 %) at a dosage of 40 mg/kg, coupled none obvious adverse reactions were observed. Collectively, LD-1, characterized by its novel structure, high potency, and selectivity as an MST3 inhibitor, showcases substantial potential for further investigation and therapeutic development.

Keywords

Anti-tumor; Ciprofloxacin; Drug repurposing; MST3; Riluzole.

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