Protein Metalation by Inorganic Anticancer Drugs

Today, there is a growing awareness that proteins, beyond nucleic acids, represent primary druggable targets for anticancer metal‐based agents. Indeed, it has been unambiguously ascertained that the coordinative binding of metal‐based drugs to selected proteins (the so‐called protein metalation process) plays a key role in the mechanism of action of a variety of inorganic anticancer agents, for example, some gold‐ and ruthenium‐based drugs. Through an innovative investigation strategy, developed in our laboratories, that is mostly based on the combined use of electrospray ionization mass spectrometry (ESI MS) and X‐ray crystallography on the same metallodrug/protein system, it is now possible to elucidate in depth the metalation process of a variety of proteins; a few instructive examples of metallodrug–protein adducts are herein provided. In turn, metalation may result in protein loss of function and may initiate a cascade of cellular processes eventually leading to cancer cell death. Trends and regularities observed in the protein modification process are highlighted, and their possible biological implications are considered. The perspectives for future work aimed at elucidating the actual molecular mechanisms of innovative metal‐based agents, their interactions with proteins, and the actual patterns of protein metalation are critically discussed in the frame of the emerging omics sciences and technologies.