Harnessing DNA minor groove binding for cancer therapy: An overview

Minor groove binders (MGBs) are a distinctive class of potential anticancer agents that are characterized by high sequence-selectivity interactions with the DNA minor groove. Their effects extend beyond the cytotoxic consequences to profound effects on gene transcription, epigenetic modulation, and DNA repair. Advances in the design and development of MGBs have expanded their spectrum to include cancer management, with recent pharmacological studies being indicative of their promising anticancer characteristics. This review provides a comprehensive overview of the MGBs and their DNA binding mechanisms. It integrates the current knowledge on how sequence-specific DNA recognition translates into downstream biological responses relevant to cancer therapy. It also highlights how their sequence-specific interactions disrupt the function of essential proteins involved in critical cellular processes, including polymerases, transcription factors, and topoisomerases. Furthermore, the review discusses how MGBs perturb the cellular microenvironment, induce DNA damage, and alter epigenetic regulation, collectively influencing cell cycle progression and ultimately triggering apoptotic pathways. Particular emphasis is placed on the molecular determinants of reduced sensitivity and resistance to MGBs, including alterations in DNA sequence, epigenetic landscape, and DNA repair pathways, addressing an important gap in understanding the therapeutic effects of these compounds at the cellular levels. Finally, the review highlights future advances in this field and the requirement for integrating DNA sequence specificity with a system-level understanding of cellular responses to minor groove binding.