An Anticancer Rhenium Tricarbonyl Targets Fe-S Cluster Biogenesis in Ovarian Cancer Cells
- Author(s)
- Benjamin Neuditschko, A. Paden King, Zhouyang Huang, Lukas Janker, Andrea Bileck, Yasmin Borutzki, Sierra C. Marker, Christopher Gerner, Justin J. Wilson, Samuel M. Meier-Menches
- Abstract
Target identification remains a critical challenge in inorganic drug discovery to deconvolute potential polypharmacology. Herein, 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 distinct dose-dependent targets with concentrations of competitive saturation between 0.1 and 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 competitively saturated 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.
- Organisation(s)
- Department of Inorganic Chemistry, Department of Analytical Chemistry, Joint Metabolome Facility, Mass Spectrometry Centre
- External organisation(s)
- Cornell University, National Institutes of Health (NIH), IMC Fachhochschule Krems
- Journal
- Angewandte Chemie (International Edition)
- Volume
- 61
- No. of pages
- 8
- ISSN
- 1433-7851
- DOI
- https://doi.org/10.1002/anie.202209136
- Publication date
- 10-2022
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 301904 Cancer research, 106037 Proteomics
- Keywords
- ASJC Scopus subject areas
- General Chemistry, Catalysis
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/4a1a14b6-47e5-43a2-988b-2b4205fe530e