An Anticancer Rhenium Tricarbonyl Targets Fe-S Cluster Biogenesis in Ovarian Cancer Cells

Benjamin Neuditschko, A. Paden King, Zhouyang Huang, Lukas Janker, Andrea Bileck, Yasmin Borutzki, Sierra C. Marker, Christopher Gerner, Justin J. Wilson (Korresp. Autor*in), Samuel M. Meier-Menches (Korresp. Autor*in)

Veröffentlichungen: Beitrag in FachzeitschriftArtikelPeer Reviewed

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.
OriginalspracheEnglisch
Aufsatznummere202209136
Seitenumfang8
FachzeitschriftAngewandte Chemie (International Edition)
Jahrgang61
Ausgabenummer43
DOIs
PublikationsstatusVeröffentlicht - 24 Okt. 2022

ÖFOS 2012

  • 301904 Krebsforschung
  • 106037 Proteomik

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