Design and development of mutant EGFR inhibitors from a structural perspective

Molecules targeting non-small cell lung cancer driven by activating mutations within the epidermal growth factor receptor (EGFR) are highly effective but acquired drug resistance remains a persistent challenge. Insights from structural pharmacology and medicinal chemistry have aided in detailed understanding of the structural basis for how these inhibitors gain their mutant EGFR selective inhibitory activity and inform state-of-the-art drug design. The novel third-generation EGFR tyrosine kinase inhibitor (TKI) YH25448 (lazertinib) binds to EGFR with T790M-targeting van der Waals interactions and intramolecular hydrogen bonds consistent with improved medicinal chemistry properties compared to AZD9291 (osimertinib). Additionally, fourth-generation TKIs targeting the drug resistant C797S mutation comprise diverse structural features, but all share hydrogen bonding capabilities with the K745 catalytic residue consistent with stronger binding. Finally, inspired by the synergy seen between ATP and allosteric inhibitors, bivalent EGFR inhibitors have emerged showing potential for compounds with structurally diverse binding modes. Insights from these combined structural and functional studies offer key insights into the development of next-generation EGFR TKIs and inspire further exploration of similar binding features more broadly in protein kinases.