Year: 2022
Type: article
Abstract: 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 the nature of lazertinib inhibition, 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 EGFR with a distinctive pyrazole moiety enabling hydrogen bonds and van der Waals interactions facilitated through hydrophilic amine and hydrophobic phenyl groups, respectively. Biochemical assays and cell studies confirm that lazertinib effectively targets EGFR(L858R/T790M) and to a lesser extent HER2. The molecular basis for lazertinib inhibition of EGFR reported here highlights previously unexplored binding interactions leading to improved medicinal chemistry properties compared to clinically approved osimertinib (AZD9291) and offers novel strategies for structure-guided design of tyrosine kinase inhibitors.
Source: ACS Medicinal Chemistry Letters
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Roswell Park Alliance Foundation, Roswell Park Cancer Institute, State University of New York, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, National Institutes of Health, NIH Office of the Director, National Cancer Institute, National Institute of General Medical Sciences, NIH Clinical Center, National Center for Advancing Translational Sciences, Argonne National Laboratory, Brookhaven National Laboratory
Awards: G1021286281, G107546177, G1313983767, G1664757510, G215985982, G2164036156, G2257902913, G2532469498, G2853181762, G3075337988, G3479632140, G3935514931, G4429385918, G5382207646, G5384392517, G5534353644, G5535608740, G5607048534, G5847927864, Studies of mutant-selective allosteric inhibitors of EGFR for non-small cell lung cancer, G604848185, Modulation of cancer specific transcriptional factors with small molecules, G6137013498, G6806936059, G9000020627, G9000038451, G9000051782, G9000119994, Discovery and optimization of novel mutant-selective allosteric inhibitors of EGFR T790M, Roswell Park Cancer Center Support Grant, NE-CAT: A Resource for Advanced Macromolecular Crystallography, EXC 2180: Individualisierung von Tumortherapien durch molekulare Bildgebung und funktionelle Identifizierung therapeutischer Zielstrukturen (iFIT), G994363656
OpenAlex ID: W4308888442