Structural Basis for Inhibition of Mutant EGFR with Lazertinib (YH25448)

08 September 2022, Version 2
This content is a preprint and has not undergone peer review at the time of posting.


Lazertinib (YH25448) is a novel third-generation tyrosine kinase inhibitor (TKI) developed as a treatment for EGFR mutant non-small cell lung cancer. To better understand lazertinib inhibition at the molecular level, we determined crystal structures of lazertinib in complex with both WT and mutant EGFR and compared its binding mode to that of structurally-related EGFR TKIs. We observe that lazertinib binds with the novel pyrazole moiety involved in hydrogen bonds and van der Waals interactions consistent with drug potency and T790M mutant selectivity. Biochemical assays and cell studies confirm that lazertinib effectively targets EGFR(L858R/T790M) and to a lesser extent against HER2 as consistent with an improved toxicity profile. The molecular basis for lazertinib inhibition of EGFR reported here highlights new strategies for structure-guided design of tyrosine kinase inhibitors.


Lung cancer
targeted therapy
kinase inhibitor
epidermal growth factor receptor
structural biology

Supplementary materials

Supplementary Information
Experimental methods, crystallographic data collection and refinement statistics, and supplemental images.


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