Covalent EGFR Inhibitors: Binding Mechanisms, Synthetic Approaches, and Clinical Profiles

Being overexpressed in several types of cancer, the epidermal growth factor receptor (EGFR) is considered one of the key therapeutic targets in oncology. Although many first‐generation EGFR inhibitors had been FDA approved for the treatment of certain types of cancer, patients soon developed resistance to these reversible ATP competitive inhibitors via mutations in the kinase domain of EGFR. A new trend was adopted to design covalent irreversible inhibitors, that is, second‐ and third‐generation inhibitors. Second‐generation inhibitors can inhibit the mutant forms but, unfortunately, they had dose limiting side effects due to wild‐type EGFR inhibition. Third‐generation inhibitors emerged shortly, which were capable of inhibiting the mutant forms exclusively while sparing the wild type. Many other strategies have also been developed to reduce the risk of covalent interactions with off‐targets, thus improving the pharmacokinetic and/or pharmacodynamic profile of the antiproliferative agents. In this review, we focused mainly on second‐ and third‐generation EGFR inhibitors, their binding mechanisms (either docking studies or co‐crystallized structures), their synthetic approaches, clinical profiles, and limitations. Covalent EGFR inhibitors were designed to overcome the resistance that had developed against the first‐generation reversible inhibitors. They have the main pharmacophoric features plus a Michael acceptor group responsible for covalent bonding with cysteine residues, leading to ultimate EGFR activity blockage. This review focuses on second‐ and third‐generation covalent EGFR inhibitors, their binding mechanisms, synthetic approaches, and clinical profiles.