Design, synthesis and biological evaluation of novel imidazo[1,2-a]pyrazine derivatives as potent SYK inhibitors for solid tumor therapy.

Spleen tyrosine kinase (SYK) has emerged as a promising therapeutic target for cancer treatment. In this study, based on the lead compound Lanraplenib, a series of novel imidazo[1,2-a]pyrazine derivatives were designed and synthesized through structure-based optimization focusing on modifications at the solvent-exposed C-8 position. The synthesized compounds were evaluated for their in vitro SYK inhibitory activity, and most of them exhibited improved potency. Among them, compound B13 showed the highest activity with an IC50 value of 10.9 nM, comparable to Lanraplenib. In vitro studies demonstrated that B13 displayed significant anti-proliferative effects against SKOV3, MDA-MB-231 and HepG2 cells, and effectively inhibited colony formation. Mechanistic studies revealed that B13 induced S phase cell cycle arrest and promoted apoptosis in a dose-dependent manner. Molecular docking suggested that the enhanced activity of B13 may be attributed to enhanced hydrophobic interactions and additional hydrogen bonding within the SYK binding pocket. Furthermore, B13 exhibited moderate metabolic stability in liver microsomes. In vivo studies using a SKOV3 xenograft model demonstrated that B13 significantly inhibited tumor growth in a dose-dependent manner, with tumor inhibition rates of 58.62% and 66.97% at 30 and 60 mg/kg, respectively, better than Lanraplenib, while showing no obvious toxicity. Collectively, these findings identify B13 as a promising SYK inhibitor and provide valuable insights for the further development of SYK targeted therapeutics for solid tumors.