The potential for new and resilient anti-cancer drugs based upon minor groove binders for DNA

Abstract

Anti-infective and anticancer drugs share the serious problem that over time resistance develops to their effects leading to clinical obsolescence. Research at the University of Strathclyde has discovered a platform of anti-infective drugs based upon minor groove binders for DNA that have exceptional resilience to the development of resistance in their target organisms (bacteria, fungi, and parasites). This property is associated with the fact that the Strathclyde minor groove binders (S-MGBs) act at more than one discrete molecular target. One of the compounds has successfully completed a phase IIa clinical trial for the treatment of Clostridioides difficile infections. Several other compounds have shown activity against a number of cancer cell lines in vitro with indications of in vivo activity in a mouse model of lung cancer. This paper places these discoveries in the context of previous studies of minor groove binders as anticancer agents and considers whether the benefits of multitargeting successfully demonstrated in anti-infective applications can be translated to anticancer applications.

Insights into the Spectrum of Activity and Mechanism of Action of MGB-BP-3

“…Their favorable cytotoxicity profiles to mammalian cells give them selectivity indices that make them suitable for development as novel drugs. This has enabled extensive in vitro and several in vivo experiments to provide proof of concept for S-MGBs as a novel class of anti-infective agent against bacterial, fungal, viral, and parasitic infections. − One of these compounds, MGB-BP-3 (Figure ) has successfully completed Phase IIa clinical trials for the treatment of Clostridioides difficile associated disease (NCT03824795). MGB-BP-3 also has potent (<1 μg/mL) antibacterial activity against methicillin-resistant and methicillin-susceptible Staphylococcus spp., Streptococcus spp., and vancomycin-resistant and vancomycin-susceptible Enterococcus spp .…”