Covalent epidermal growth factor receptor (EGFR) inhibitors in targeted therapy of drug-resistant non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is the main subtype of lung cancer and is a common cause of cancer-related mortality worldwide. Mutations in the epidermal growth factor receptor (EGFR) gene play a leading role in the pathogenesis of NSCLC, causing its pathological activity. The first generation of EGFR inhibitors, acting reversibly, effectively block the effects of EGFR with activating mutations by benefiting from competition with adenosine triphosphate for binding to the kinase. However, after several months of treatment, a secondary T790M mutation often occurs, causing resistance to subsequent therapy with these drugs. Effective inhibition of EGFR with the T790M mutation was possible due to second-generation inhibitors acting via a covalent mechanism. However, the second generation of covalent inhibitors has received limited use in therapy due to insufficient selectivity for EGFR T790M and a narrow therapeutic window. The discovery of covalent pyrimidine-based inhibitors has led to the emergence of a number of effective and safer third-generation drugs for the treatment of NSCLC with the EGFR T790M mutation. This review contains a brief description of first- and second-generation EGFR inhibitors and a detailed discussion of the main stages in the development of third-generation inhibitors. The main emphasis is placed on the identified “structure–activity” patterns. Data are provided on inhibitors that have received the status of approved drugs for the treatment of NSCLC. Promising directions for the development of novel EGFR inhibitors are indicated.