Combination therapy employing drugs with complimentary mechanisms of action is one of the most successful treatment strategies for cancer. This is most effective when two drugs are synergistic; they achieve a greater than additive effect towards their target disease cells. This research theme aims to develop metallocompounds for use in combination with PARP (poly ADP ribose polymerase) inhibitors (PARPi) for aggressive or drug-resistant cancers. Of special interest are Ruthenium(II) polypyridyl complexes (RPCs) that bind DNA by metallo-intercalation (the reversible insertion of a ligand between DNA base pairs), which act to stall DNA replication forks in rapidly-proliferating cancer cells without generating genotoxic double-strand break damage (see Sci. Rep. 2016). This biological activity results in PARPi drug synergy and renders triple-negative breast cancer cells hypersensitive to the FDA-approved Olaparib with minimal impact towards normal cells.

 

We propose that these identified synergistic drug combinations can: i) reduce the active dose of PARPi required for treatment and ii) expand the scope of PARPi to include a greater range of cancer types, including BRCA-proficient tumors. Together, we believe this approach can improve disease responses and overcome acquired or de novo drug resistance, a common issue with PARPi treatment.

 

Relevant publications: ACS Chem Biol 2020, ChemMedChem 2020, Sci. Rep. 2023, J. Med Chem. 2023,