Objective: Colorectal cancer (CRC) is one of the most common cancers worldwide and a major cause of cancer-related death. This study examined the potential anti-CRC effects of the novel oxindole derivatives GIF-0854-r and GIF-0856-r using network pharmacology-based target identification.

Materials and Methods: The putative molecular targets of GIF-0854-r and GIF-0856-r were identified using SwissTargetPrediction, and CRC-associated genes were collected from GeneCards. Overlapping compound-disease targets were determined using Venn diagrams and subjected to protein-protein interaction analysis using STRING and Cytoscape. The predicted compound targets were analyzed for overlap with CRC genes, revealing 150 gene targets.

Results: The PPI network predicted hub targets including STAT3, CASP3, HIF1α, GSK3β, ERBB2, MMP9, PARP1, PRKACα, PIK3Cα, and IGF1R. Pathway enrichment revealed proteoglycans in cancer, pathways in cancer, the HIF1 signaling pathway, apoptosis, responses to oxidative stress, ATP binding, kinase binding, transcription factor binding, and tyrosine kinase activity. The results of disease association revealed predicted hub targets that are linked with colorectal neoplasms and other cancer diseases. Molecular docking showed competent ligand-binding efficiency of GIF-0854-r and GIF-0856-r with the active site of GSK3β.

Conclusions: The results provide evidence that GIF-0854-r and GIF-0856-r may have multitarget anti-CRC effects by regulating critical oncogenic, apoptotic, hypoxia-, oxidative stress-, and kinase-specific signaling pathways.