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 basis for how these inhibitors gain their mutant EGFR selective inhibitory activity inform state-of-the-art design. The novel third-generation tyrosine kinase inhibitor (TKI) YH25448 (lazertinib) binds to with T790M-targeting van der Waals interactions intramolecular hydrogen bonds consistent improved properties compared AZD9291 (osimertinib). Additionally, fourth-generation TKIs resistant C797S mutation comprise diverse features, all share bonding capabilities K745 catalytic residue stronger binding. Finally, inspired synergy seen between ATP allosteric inhibitors, bivalent emerged showing potential compounds structurally binding modes. combined functional studies offer key insights into development next-generation inspire further exploration similar features more broadly protein kinases.