Exploring the Impact of Two DNA Minor Groove Binder Compounds on HCT-116 Cells: A Comprehensive Multiomics Analysis Using Mass Spectrometry

Colorectal cancer (CRC) remains a major global health burden, necessitating innovative therapeutic approaches with improved selectivity and reduced toxicity. DNA minor groove binders (MGBs) represent a promising class of agents that modulate DNA-associated processes without inducing permanent DNA damage. In this study, two previously reported distamycin-like DNA minor groove binders, MGB30 and MGB32, were investigated to elucidate their molecular mechanisms of action in HCT-116 human colorectal cancer cells. An integrated multiomics approach combining metabolomics and proteomics was employed using TIMS-QTOF-UHPLC-MS. Four biological replicates were used for each treatment condition. Following MGB30 treatment, 12 metabolites and 187 proteins were significantly dysregulated, whereas MGB32 treatment resulted in alterations of 41 metabolites and 409 proteins using a Student’s t-test with q-value <0.05. Pathway enrichment analysis revealed that both compounds significantly disrupted purine metabolism, while MGB32 additionally affected beta-alanine metabolism, glutathione metabolism, and spermidine and spermine biosynthesis. Proteomic analysis further demonstrated deactivation of RNA processing, translation, and ribosome biogenesis, leading to impaired protein synthesis and reduced cancer cell proliferation. This study provides mechanistic insights into the downstream molecular effects of MGB30 and MGB32 that disrupt key mechanisms underlying tumor growth, offering new avenues for CRC treatment.