Metal-Tyrosine Kinase Inhibitors: Targeted metal-drug conjugates

Tyrosine Kinases are enzymes that catalyse the phosphorylation of the tyrosine residues of their sub-strates 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 resis-tance 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, advance-ments over the past decade in the field of metal based-TKi conjugates are discussed and insights are pro-vided 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.(c) 2022 Elsevier B.V. All rights reserved.

Automated summary

Tyrosine Kinases play a crucial role in cancer, but small molecule Tyrosine Kinase Inhibitors face limitations in clinical usage. Metal-Tyrosine Kinase Inhibitor conjugates have emerged as a promising area of research to overcome these limitations, with potential applications in multiple biological fields.