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

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.