Title : Half-sandwich iridium(III) complexes mechanism of action for anti-cancer therapy: Cytoskeletal proteins and heat-shock proteins as privileged protein targets
Abstract:
The identification of intracellular targets of anticancer drug candidates provides key information on their mechanism of action. (C^N)-chelated half-sandwich iridium(III) complexes are currently being investigated for their anti-proliferative and pro-apoptotic capacity, both linked to their pro-oxidant activity and ability to raise intracellular levels of hydrogen peroxide, to which tumour cells are more sensitive. We have previously shown that this class of molecules is also capable of reacting with amino acids and forming protein adducts in the cellular environment, thus providing a new mechanism of action explaining their cytotoxicity. I will discuss the different approaches we have undertaken to analyse the intracellular fate of such complexes, either in an unbiased manner, through X-ray fluorescence imaging of iridium, or through chemical modification allowing indirect fluorescent imaging (molecule appended by Bodipy and use of click-chemistry). I will also discuss (i) our recent identification of a range of protein targets, through a click-and-capture assay with a clickable half-sandwich (C^N) iridium(III) complex, and (ii) how the iridium-based complex modifies chaperone proteins involved in protein folding and the actin cytoskeleton. Collectively, these results open a new avenue for the development of half-sandwich iridium-based anticancer drugs.
Audience Take-Away:
- The presentation will present robust methods to visualize a metal-based drug in cellulo (XRF) but also methods that can be expanded to metal-devoid drugs, in order to visualize the molecule in cells (through click chemistry) and to colocalise its targets (with a proximity-ligation assay)
- These approaches are particularly suited to chemists interested in medicinal chemistry and preclinical approaches
- It is a Research that other faculty could use to expand their research or teaching.
- This provides a practical solution to a problem that could simplify or make a designer’s job more efficient
- It will improve the accuracy of a design, or provide new information to assist in a design problem, for example through the illustration of a proteomic approach to click-and capture protein targets of a given drug
- The approaches and results are relevant to studies dealing with chemical reactivities of molecules in vivo in the cellular context (through oxidative and electrophilic stresses)
