Globally Approved EGFR Inhibitors: Insights into Their Syntheses, Target Kinases, Biological Activities, Receptor Interactions, and Metabolism

Abstract

Targeting the EGFR with small-molecule inhibitors is a confirmed valid strategy in cancer therapy. Since the FDA approval of the first EGFR-TKI, erlotinib, great efforts have been devoted to the discovery of new potent inhibitors. Until now, fourteen EGFR small-molecule inhibitors have been globally approved for the treatment of different types of cancers. Although these drugs showed high efficacy in cancer therapy, EGFR mutations have emerged as a big challenge for these drugs. In this review, we focus on the EGFR small-molecule inhibitors that have been approved for clinical uses in cancer therapy. These drugs are classified based on their chemical structures, target kinases, and pharmacological uses. The synthetic routes of these drugs are also discussed. The crystal structures of these drugs with their target kinases are also summarized and their bonding modes and interactions are visualized. Based on their binding interactions with the EGFR, these drugs are also classified into reversible and irreversible inhibitors. The cytotoxicity of these drugs against different types of cancer cell lines is also summarized. In addition, the proposed metabolic pathways and metabolites of the fourteen drugs are discussed, with a primary focus on the active and reactive metabolites. Taken together, this review highlights the syntheses, target kinases, crystal structures, binding interactions, cytotoxicity, and metabolism of the fourteen globally approved EGFR inhibitors. These data should greatly help in the design of new EGFR inhibitors.

Clinical sequencing identifies potential actionable alterations in a high rate of urachal and primary bladder adenocarcinomas

“…EGFR is a widely used therapeutic target. To date, numerous anti-EGFR compounds, both tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, have been developed and approved for different cancers (32). This is also re ected by our results identifying the second highest number of recommended drugs for patients with tumours harboring an EGFR ampli cation.…”

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“…[39] The interaction between EGFR and STAT3 occurs in the nucleus upon ligand-dependent EGFR activation. [42] Given that SH2 containing proteins can dock with phosphorylated tyrosine residues on EGFR, [43] SHF is expected to be a impedance **p < 0.01). The relative quantification of STAT3/DNMT1 interaction was listed.…”

Potential Therapeutics Targeting Upstream Regulators and Interactors of EHMT1/2

“…EGFR inhibitors are classified into two broad categories: irreversible or reversible. Irreversible inhibitors such as Afatinib, Neratinib, and Dacomitinib covalently bind to a cysteine residue on EGFR [ 60 ]. In contrast, reversible EGFR inhibitors such as Erlotinib, Lapatinib, and Gefitinib compete with ATP for the ATP binding pocket on EGFR without establishing any covalent interaction [ 59 , 60 ].…”

“…Irreversible inhibitors such as Afatinib, Neratinib, and Dacomitinib covalently bind to a cysteine residue on EGFR [ 60 ]. In contrast, reversible EGFR inhibitors such as Erlotinib, Lapatinib, and Gefitinib compete with ATP for the ATP binding pocket on EGFR without establishing any covalent interaction [ 59 , 60 ]. In a recent study, Erlotinib and the HDAC inhibitor SAHA displayed synergistic efficacy against mucoepidermoid carcinoma [ 176 ].…”