Computational and Experimental Verification of Cabozantinib Targeting DDX11 to Inhibit DNA Damage Repair in Liver...

Phosphorylation of serine residues within SQ/TQ motifs, particularly Ser237 of the ATP-dependent DNA helicase DDX11, by ataxia telangiectasia mutated (ATM) kinase plays a key role in activating the DNA damage response (DDR) in liver cancer. To disrupt this signaling pathway, we applied a computationally guided drug repurposing approach to identify FDA-approved compounds capable of targeting critical DDX11 residues. A library of 2367 drugs was screened using a structure-based, site-specific docking strategy, yielding seven candidates with binding affinities from -6.5 to -7.7 kcal/mol. Although Afatinib showed the strongest docking score (-7.674 kcal/mol), it lacked hydrogen-bond interactions with Ser237 and Gln238 and was therefore excluded. In contrast, dacomitinib, ergotamine, and cabozantinib displayed both favorable affinities and stable hydrogen-bonding with these key residues. Comprehensive molecular dynamics simulations (100 ns) confirmed the conformational stability of the selected complexes, while MM-GBSA/MM-PBSA and principal component analyses supported strong and persistent binding. Among them, cabozantinib was prioritized for experimental validation due to its clinical relevance in hepatocellular carcinoma and selective interaction with Ser237. Proteomic profiling further revealed that cabozantinib downregulates DNA repair proteins and attenuates homologous recombination (HR) repair capacity in liver cancer cells. Together, computational and experimental findings indicate that targeting DDX11, particularly at Ser237, may effectively suppress ATM-mediated DDR signaling and impede liver cancer progression, warranting further preclinical and clinical evaluation.