Metal-Tyrosine Kinase Inhibitors: Targeted metal-drug conjugates

Tyrosine Kinases are enzymes that catalyse the phosphorylation of the tyrosine residues of their substrates and activate downstream pathways involved in cellular proliferation. Their overexpression/hyper-activity is implicated in numerous different cancerous cell lines. Small molecule Tyrosine Kinase Inhibitors (TKi’s), such as Imatinib, Erlotinib and Sunitinib have been developed as targeted anti-cancer therapeutics but, at the moment, their clinical usage is hindered due to acquired and innate resistance and/or dose limiting side effects. Recently, Metal-Tyrosine Kinase Inhibitor conjugates have become a promising field to overtake these drawbacks since the TKi’s show potential to improve selectivity and pharmacological properties of metal-based drugs, overcoming the resistance associated with current TKi’s. Metal-Tyrosine Kinase Inhibitor conjugates further find applications in several biological fields as dual-modal activity drugs, pro-drug systems and selective metal theragnostics. In this review, advancements over the past decade in the field of metal based-TKi conjugates are discussed and insights are provided to successfully develop metal – TKi conjugates. Four main TK targets are discussed here: EGFR (Epidermal Growth Factor Receptor), BCR-ABL (Breakpoint Cluster Region – Abelson Kinase), PDGFR (Platelet Derived Growth Factor Receptor) and VEGFR (Vascular Endothelial Growth Factor Receptor). Future perspectives and applications of this promising research area are also outlined.