From challenges to solutions: A review of fourth-generation EGFR tyrosine kinase inhibitors to overcome the C797S triple mutation in non-small cell lung cancer.

This Review discusses recent advancements in the development of fourth-generation "Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs)" targeting resistance mutations, with an emphasis on the C797S mutation in "Non-small Cell Lung Cancer (NSCLC)". While first, second, and third-generation EGFR-TKIs have made significant progress in overcoming EGFR kinase resistance, the emergence of the EGFR-C797S mutation poses a substantial challenge, particularly in the context of resistance to Osimertinib. Fourth-generation TKIs are classified into ATP-competitive, allosteric, and ortho-allosteric inhibitors, with the goal of enhancing specificity for mutant EGFR while minimizing off-target effects on wild-type EGFR to reduce toxicity. This Review provides a detailed analysis of structural modifications and their impact on drug potency and selectivity, with the aim of improving efficacy against resistant NSCLC. Preclinical and early-phase clinical trials of these inhibitors are promising, though further optimization of pharmacokinetic and safety profiles is crucial for future clinical success. This work offers key insights for medicinal chemists in the design and development of fourth-generation EGFR inhibitors to address drug-resistant mutations in NSCLC.