Orthoallosteric EGFR‐TKIs: A New Paradigm in NSCLC Treatment Strategy Targeting the C797S Mutation

ABSTRACT The remarkable clinical success of third‐generation epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) has significantly advanced the treatment landscape for non‐small‐cell lung cancer (NSCLC). However, the emergence of the tertiary point mutation C797S poses a substantial obstacle to their clinical efficacy, leading to a dearth of FDA‐approved targeted therapies for patients harboring this mutation. Addressing this pressing clinical challenge necessitates the development of novel therapeutic agents targeting the clinically challenging EGFR mutation. This review delves into the design strategies, antitumor activity, and crucial protein–drug interactions of recently introduced Orthoallosteric fourth‐generation EGFR‐TKIs. These inhibitors are distinguished by their ability to simultaneously engage both the canonical orthosteric (ATP) binding site and the allosteric site. By shedding light on these key aspects, the review serves as a valuable resource for medicinal chemists, empowering them to propel the advancement of fourth‐generation EGFR inhibitors.