Multi-omics approaches to unravel the biological effects of DNA-binding small molecules

DNA-targeting ligands comprise a diverse class of molecules that bind either canonical duplex DNA or non-canonical DNA structures such as G-quadruplexes. The recent shift towards combining distinct omics approaches, including epigenomics, transcriptomics, proteomics, and metabolomics, is significantly expanding the understanding of the biological effects induced by these small molecules, capturing complex cellular perturbations across multiple molecular layers. Here, we report representative examples from recent literature that illustrate how multi-omics approaches have helped to uncover previously unrecognised mechanisms underlying therapeutic efficacy, chemoresistance, toxicity, and chromatin remodelling induced by DNA-binding compounds. Finally, we address key computational bottlenecks in multi-omics data integration and highlight emerging in situ target-engagement mapping strategies that could bridge direct drug occupancy at genomic sites with downstream biological outcomes.