An Anticancer Rhenium Tricarbonyl Targets Fe-S Biogenesis in Ovarian Cancer Cells – Pull-Down

Target identification remains a critical challenge in inorganic drug discovery to deconvolute potential polypharmacology. Here, we describe an improved approach to prioritize candidate protein targets based on a combination of dose-dependent chemoproteomics and treatment effects in living cancer cells for the rhenium tricarbonyl compound TRIP. Chemoproteomics revealed 89 dose-dependent targets with competing concentrations between 0.1–32 µM despite the broad proteotoxic effects of TRIP. Target response networks revealed two highly probable targets of which the Fe-S cluster biogenesis factor NUBP2 was competed by free TRIP at nanomolar concentrations. Importantly, TRIP treatment led to a down-regulation of Fe-S cluster-containing proteins and upregulated ferritin. Fe-S cluster depletion was further verified by assessing mitochondrial bioenergetics. Consequently, TRIP emerges as a first-in-class modulator of the scaffold protein NUBP2, which disturbs Fe-S cluster biogenesis at sub-cytotoxic concentrations in ovarian cancer cells.