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The organometallic AuI bis‐N‐heterocyclic carbene complex [Au(9‐methylcaffeine‐8‐ylidene)2]+ (AuTMX2) was previously shown to selectively and potently stabilise telomeric DNA G‐quadruplex (G4) structures. This study sheds light on the molecular reactivity and mode of action of AuTMX2 in the cellular context using mass spectrometry‐based methods, including shotgun proteomics in A2780 ovarian cancer cells. In contrast to other metal‐based anticancer agents, this organogold compound is less prone to form coordinative bonds with biological nucleophiles and is expected to exert its drug effects mainly by non‐covalent interactions. Global protein expression changes of treated cancer cells revealed a multimodal mode of action of AuTMX2 by alterations in the nucleolus, telomeres, actin stress‐fibres and stress‐responses, which were further supported by pharmacological assays, fluorescence microscopy and cellular accumulation experiments. Proteomic data are available via ProteomeXchange with identifier PXD020560. [ABSTRACT FROM AUTHOR]

A cationic AuI N‐heterocyclic carbene complex featuring caffeine‐based ligands has shown potent and selective anticancer effects in ovarian cancer cells. This organogold compound is remarkably stable in physiological conditions. Therefore, the observed therapeutic effects are mainly due to non‐covalent interactions of the gold compound with its pharmacological targets. Among the latter, DNA secondary structures—G‐quadruplexes—play a pivotal role in the mechanisms of anticancer action. More information can be found in the Full Paper by S. M. Meier‐Menches, A. Casini, C. Gerner, et al. on page 15528. [ABSTRACT FROM AUTHOR]