Design, Synthesis Optimization and Anticancer Activity of Small Molecule Kinase Inhibitors

Jialiang Sun, Tong Li, Xi Chen, Cheng Peng, Lu Liu, Baorong Hu and Shuang Zhao

Background and Objective: The development of inhibitors targeting protein kinases (PKs) has emerged as a pivotal field in drug research. In this context, a comprehensive analysis of kinase structural attributes has led to the proposal of a pyrimidine-linked biphenyl core (PBC) pharmacophore model aimed at bridging the adenine-binding region and the hydrophobic pocket left vacant by the DFG segment rotation. Materials and Methods: Building upon this, a Suzuki One-Pot Reaction was employed to synthesize 20 derivative compounds, among which F1 and F2 exhibited heightened tumor inhibitory potential (IC₅₀<10 μM). These synthesized compounds were subjected to a Thiazolyl Blue (MTT) assay to assess their impacts on cell proliferation. Meanwhile, the in vivo anticancer effects were validated through rat tumor xenograft experiments. Immunofluorescence staining of tumor tissues in rats was utilized to observe DNA damage and cell apoptosis. Additionally, liver and kidney tissues were subjected to Hematoxylin-Eosin (H&E) staining to evaluate the influence of the inhibitors on rat liver and kidney cells. Results: The pronounced antiproliferative capabilities of F1 and F2 against tumor cells, while exerting minimal influence on normal human cells, indicating substantial tumor cell-selective toxicity (p<0.001). After 24 hrs of exposure to F1 and F2, a notable increase in tumor cell apoptosis was observed, with MTT assays showing an IC₅₀ of 2.9 μm for F1 and 8.0 μm for F2, signifying significant tumor cell inhibition. Compared to the control (Ctrl) group, the levels of γH2AX signal and relative protein expression in the F1 and F2 group were significantly higher (p<0.001). However, there were no significant toxic side effects observed in the rat liver and kidney tissues (p>0.001). Conclusion: In summary, the PBC pharmacophore model opened novel avenues for developing relevant drugs for PK inhibitors. In the future, compound design and optimization based on this model hold promise for delivering new effective drugs for diseases like cancer.

View Fulltext Back