Results and Discussion. To characterize the binding mode of lazertinib in complex with the EGFR kinase domain, we determined a 2.4 Å resolution X-ray co-crystal structure of lazertinib soaked into WT EGFR crystals (Figure & S1, PDB ID 7UKV). WT kinase domains crystallize in the active "ɑC-helix in" conformation due to crystal packing of the kinase domains as asymmetric dimers. As expected, lazertinib binds with the aminopyrimidine anchored to the hinge region by H-bonds to M793 and covalent bond formed at C797 as generally observed for third-generation TKIs. Importantly, the unique pyrazole group extends away from the hinge in a conformation that positions the phenyl ring toward the K745-E762 salt bridge and the N,N-dimethylmethyleneamine (methyleneamine) in a H-bond with the DFG-motif D855 carboxylate. The substituted pyrazole of lazertinib is unique among third-generation EGFR TKIs and most likely the basis for mutant-selectivity and improved medicinal chemistry properties. A comparison of our structures from the "ɑC-helix in" active WT (Figure ) and "ɑC-helix out" inactive T790M (Figure ) show very similar binding positions indicating that lazertinib is anchored to the EGFR kinase domain identically in both active and inactive states and independent of the Thr versus Met 790 gatekeeper residue (Figure ). We expect that this conformation of lazertinib is preferred as compared to the "flipped" conformation (Figure ) in the "ɑC-helix in" active state due to the requirement to anchor the positive methyleneamine near the K745-E762 salt bridge (Figure ).