Metallodrugs and drug synergy
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. 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
Luminescent metal complexes in FRET binding assays
Metal polypyridyl complexes have long been of interest for their ability to emit from triplet MLCT (metal to ligand charge-transfer) excited states. This is characterised by long lifetimes and large Stokes shift values and has found numerous applications, such as in biomolecular binding, cellular imaging and organic light-emitting diodes (OLEDs). We are interested in the design of MLCT-emissive metal polypyridyl complexes for these applications and, indeed, any novel use of MLCT emission. For example, we have shown that MLCT luminescence can undergo FRET (Forster Resonance Energy Transfer) with the organic dye Cyanine 5.5 to form mega-Stokes shift FRET pairs. This provides a simple and rapid technique to examine binding with biomolecules. As FRET provides a measure of the distance between donor and acceptor, information on binding site at the nm scale can be obtained. Molecules characterised by this process can also be assessed for their biological activity to link with work above.
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Relevant publications: J Am Chem Soc 2023, Dalton Trans 2024, Chem Soc Rev 2025