Cyclometalated Gold(III) Complexes Containing N‐Heterocyclic Carbene Ligands Engage Multiple Anti‐Cancer Molecular Targets

Metal N‐heterocyclic carbene (NHC) complexes are a promising class of anti‐cancer agents displaying potent in vitro and in vivo activities. Taking a multi‐faceted approach employing two clickable photoaffinity probes, herein we report the identification of multiple molecular targets for anti‐cancer active pincer gold(III) NHC complexes. These complexes display potent and selective cytotoxicity against cultured cancer cells and in vivo anti‐tumor activities in mice bearing xenografts of human cervical and lung cancers. Our experiments revealed the specific engagement of the gold(III) complexes with multiple cellular targets, including HSP60, vimentin, nucleophosmin, and YB‐1, accompanied by expected downstream mechanisms of action. Additionally, PtII and PdII analogues can also bind the cellular proteins targeted by the gold(III) complexes, uncovering a distinct pincer cyclometalated metal–NHC scaffold in the design of anti‐cancer metal medicines with multiple molecular targets. On target: Anti‐cancer active pincer cyclometalated gold(III) complexes containing N‐heterocyclic carbene ligands have been identified to be a type of multi‐target anti‐cancer agent by using a combined photoaffinity labelling and click chemistry approach. The PdII and PtII analogues can competitively bind to the same cellular targets.