Identification of Cellular Protein Targets of a Half-Sandwich Iridium(III) Complex Reveals Its Dual Mechanism of Action via Both Electrophilic and Oxidative Stresses - Institut de Biologie Paris Seine Access content directly
Journal Articles Journal of Medicinal Chemistry Year : 2024

Identification of Cellular Protein Targets of a Half-Sandwich Iridium(III) Complex Reveals Its Dual Mechanism of Action via Both Electrophilic and Oxidative Stresses

Robin Ramos
Joëlle Sobczak-Thépot

Abstract

Identification of intracellular targets of anticancer drug candidates provides key information on their mechanism of action. Exploiting the ability of the anticancer (C∧N)-chelated half-sandwich iridium(III) complexes to covalently bind proteins, click chemistry with a bioorthogonal azido probe was used to localize a phenyloxazoline-chelated iridium complex within cells and profile its interactome at the proteome-wide scale. Proteins involved in protein folding and actin cytoskeleton regulation were identified as high-affinity targets. Upon iridium complex treatment, the folding activity of Heat Shock Protein HSP90 was inhibited in vitro and major cytoskeleton disorganization was observed. A wide array of imaging and biochemical methods validated selected targets and provided a multiscale overview of the effects of this complex on live human cells. We demonstrate that it behaves as a dual agent, inducing both electrophilic and oxidative stresses in cells that account for its cytotoxicity. The proposed methodological workflow can open innovative avenues in metallodrug discovery.
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Avant la publication
Saturday, October 5, 2024
Embargoed file
Saturday, October 5, 2024
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Dates and versions

hal-04537800 , version 1 (08-04-2024)

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Robin Ramos, Anthi Karaiskou, Candice Botuha, Sadek Amhaz, Michaël Trichet, et al.. Identification of Cellular Protein Targets of a Half-Sandwich Iridium(III) Complex Reveals Its Dual Mechanism of Action via Both Electrophilic and Oxidative Stresses. Journal of Medicinal Chemistry, inPress, ⟨10.1021/acs.jmedchem.3c02000⟩. ⟨hal-04537800⟩
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