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Herein, we describe an improved approach to prioritize candidate protein targets based on a combination of dose\u2010dependent chemoproteomics and treatment effects in living cancer cells for the rhenium tricarbonyl compound TRIP. Chemoproteomics revealed 89 distinct dose\u2010dependent targets with concentrations of competitive saturation between 0.1 and 32\u2005\u03bcM despite the broad proteotoxic effects of TRIP. Target\u2010response networks revealed two highly probable targets of which the Fe\u2212S cluster biogenesis factor NUBP2 was competitively saturated by free TRIP at nanomolar concentrations. Importantly, TRIP treatment led to a down\u2010regulation of Fe\u2212S cluster containing proteins and upregulated ferritin. Fe\u2212S cluster depletion was further verified by assessing mitochondrial bioenergetics. Consequently, TRIP emerges as a first\u2010in\u2010class modulator of the scaffold protein NUBP2, which disturbs Fe\u2212S cluster biogenesis at sub\u2010cytotoxic concentrations in ovarian cancer cells.<\/jats:p>","DOI":"10.1002\/anie.202209136","type":"journal-article","created":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T04:45:28Z","timestamp":1661402728000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["An Anticancer Rhenium Tricarbonyl Targets Fe\u2212S Cluster Biogenesis in Ovarian Cancer Cells"],"prefix":"10.1002","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7024-7493","authenticated-orcid":false,"given":"Benjamin","family":"Neuditschko","sequence":"first","affiliation":[{"name":"Department of Analytical Chemistry Faculty of Chemistry University of Vienna  1090 Vienna Austria"},{"name":"Institute of Inorganic Chemistry Faculty of Chemistry University of Vienna  1090 Vienna Austria"},{"name":"Present address: Institute Krems Bioanalytics IMC University of Applied Sciences Krems  3500 Krems Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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