Loosely bound and water-soluble ferrous iron makes up the labile iron pool (LIP) of the cell, the “cellular currency” of iron that moves between organelles of iron storage and utilization. Compared to normal cells, cancer cells harbor an elevated LIP to support their enhanced rates of proliferation, drug resistance, and stem cell maintenance. Despite increasing appreciation for the role of LIP in diverse pathologies, chemical tools to study LIP and the ferrous iron “interactome” are underdeveloped when compared to the diversity of approaches and tools available to study proteins and nucleic acids. Previous works have shown that the Adamantane-trioxolane (TRX) ring system can be activated selectively with Fe²⁺ over other divalent metal ions. Via the Fenton-like reaction, the fragment's O–O bond is cleaved, producing an oxygen-centered radical. Subsequent rearrangements or bond scission reactions produce carbon-centered radical species that can react with heme and cellular proteins. While the properties of these molecules have been optimized as antimalarials, their metal- and oxidation state-specific reactivity make them potentially valuable tools for chemical biology.
The use of ¹⁸F-TRX, a first-in-class PET radiotracer for imaging Fe²⁺ in vivo, has revealed elevated Fe²⁺ to be a common feature in castration-resistant prostate cancer (CRPC), indicating the need for an activity-based probe for proteomic-wide identification of proteins involved in this LIP interactome. Using a proteomic approach with a Fe²⁺-activable TRX probe named MiPC-1 (Mitochondria-targeting Peroxide for Chemoproteomics - 1), we identified several mitochondrial chaperones and their known interactors as the enriched targets, suggesting the mitochondrial proteostasis network as a vulnerability of CRPC.

Linh Tram

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