Identification and Validation of Small Molecule Inhibitors Targeting FGFR through Molecular Docking-Based Screening

Fibroblast growth factors and their receptors (FGFRs) play important roles in multiple cellular processes. FGFR genetic alterations such as mutations, amplifications, and chromosomal translocations are prevalent in various cancer types, contributing to the initiation and progression of tumors by enhancing FGFR signaling. Identifying effective small molecule inhibitors that selectively target FGFR can advance cancers therapy driven by FGFR abnormalities. Here, we conducted molecular docking and dynamics simulations to discover new small compounds targeting FGFRs. By docking with 2.8 million small molecules, we identified three promising FGFR inhibitors ranked in the top average absolute difference in free energy. By evaluating the binding stability of the docking pose of these three compounds, we found that ZINC000101867325 formed the most stable binding interactions with FGFRs. After treatment with ZINC000101867325, colorectal cancer cell lines showed a decrease in FGFR phosphorylation and early apoptosis. In addition, ZINC000101867325 is also predicted to interact with FGFR2 mutations in colorectal cancer (CRC) patients. This study provides the novel FGFR inhibitors, and enriches treatment strategies for cancers. We docked approximately 2.8 million small molecule drugs to the crystal structure of FGFR1-4 and predicted three small molecules targeting fgfr. Among them, ZINC000101867325 showed superior bond type and stability. The effects of ZINC000101867325 on FGFR phosphorylation and apoptosis induction in two colorectal cancer cell lines were verified by RNA-seq combined with WB and flow cytometry analysis.In the RNA-seq analysis on cells, ~100 cells were used for per reaction and two or three replicates were performed for each group.