Approaches towards understanding the mechanism-of-action of metallodrugs

Abstract Known as highly efficient metallodrugs that have been clinically used to treat various types of cancers, cisplatin and its analogues have attracted and inspired extensive interest in the development of both platinum and non-platinum drugs. However, the past years witnessed slow progress of newly approved metal-based drugs. One of the key obstacles that hamper the progress is the poor understanding of the mechanism-of-action of metal compounds which usually do not follow the drug-like principles of organic compounds and display complicated thermodynamic and kinetic reactivities. Nevertheless, unique techniques such as atomic spectroscopy, nuclear magnetic resonance, X-ray spectroscopy, emission spectroscopy, and secondary-ion mass spectrometry are available that can provide detailed information on the chemical and biological environment of metal ions/complexes. Moreover, emerging methods including chemical biology probes and multi-omics strategies have been developed which are of great merit in understanding the mechanism-of-action including the molecular target(s) of metal complexes. In this review, we summarized approaches for deciphering the mechanism-of-action of metal complexes and highlighted selected examples with in-depth mechanistic insights.