Unravelling Tinengotinib’s Mechanistic Landscape in Triple-Negative Breast Cancer Via Network Pharmacology and in Silico Simulation Techniques

Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous subtype with limited treatment options and poor clinical outcomes. Tinengotinib (TT-00420), a spectrum-selective multi-kinase inhibitor, has emerged as a promising candidate for targeting multiple dysregulated pathways in TNBC. This study employed an integrative in silico strategy—combining network pharmacology, molecular docking, molecular dynamics (MD) simulations, and binding free energy (MMGBSA) calculations—to investigate the therapeutic potential of tinengotinib. Network pharmacology revealed that tinengotinib modulates key TNBC-associated pathways, including PI3K-Akt, ErbB, and focal adhesion, which are central to proliferation, apoptosis, and therapy resistance. Molecular docking demonstrated strong binding affinities with hub proteins, particularly PTK2 (-10.7 kcal/mol), MAPK8 (-10.6 kcal/mol), EGFR (-9.5 kcal/mol), and ESR1 (-9.4 kcal/mol). MD simulations confirmed stable binding and favorable conformational dynamics across all complexes, with EGFR and PTK2 showing reduced solvent accessibility indicative of structural compaction, while ESR1, SRC, and MAPK8 displayed increased solvent exposure. MMGBSA analysis further validated the thermodynamic stability of these interactions, with PTK2 and MAPK8 exhibiting the most favorable binding free energies. Collectively, these results highlight tinengotinib’s multitarget mechanism through stable interactions with key oncogenic proteins, providing a strong molecular rationale for its continued clinical development in TNBC management.