Structural elements that enable specificity for mutant EGFR kinase domains with next-generation small-molecule inhibitors.

14 February 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Specificity for a desired enzyme target is an essential property of small-molecule inhibitors. Molecules targeting oncogenic driver mutations in the epidermal growth factor receptor (EGFR) kinase domain have had a considerable clinical impact due to their selective binding to cancer-causing mutants compared to wild type. Despite the availability of clinically approved drugs for cancers driven by EGFR mutants, persistent challenges in drug resistance in the past decades have led to newer generations of drugs with divergent chemical structures. The present clinical complications are mainly due to acquired resistance to third-generation inhibitors by the acquisition of the C797S mutation. Diverse fourth-generation candidates and tool compounds with C797S selectivity have emerged and their structural characterization has allowed for understanding of the molecular factors that allow for EGFR mutant selective binding. Here, we have reviewed all known structurally-characterized EGFR TKIs targeting clinically-relevant mutations to identify consistent binding mode features that enable C797S inhibition. Newer generation EGFR inhibitors exhibit consistent and previously underutilized hydrogen bonding interactions with the conserved K745 and D855 residue side chains. We also consider binding modes and hydrogen bonding interactions of inhibitors targeting the classical ATP and the more unique allosteric sites.


Epidermal growth factor receptor
Lung cancer
Structural Biology


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