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Identification of the Intracellular Protein Targets of a Bio-active Clickable Half-Sandwich Iridium Complex by Chemical Proteomics

Ramos, R.; Karaiskou, A.; Botuha, C.; Trichet, M.; Dingli, F.; Forte, J.; Lam, F.; Canette, A.; Chaumeton, C.; Salome, M.; Chenuel, T.; Bergonzi, C.; Meyer, P.; Bohic, S.; Loew, D.; Salmain, M.; Sobczak-Thepot, J.

2023-05-24 biochemistry
10.1101/2023.05.24.542041 bioRxiv
Show 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, HSP90 folding activity was inhibited in vitro and major cytoskeleton disorganization was observed. We used a wide array of imaging and biochemical methods to validate selected targets and obtain 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.

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"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.