7ukw

EGFR(T790M/V948R) in complex with Lazertinib (YH25448)

spinqualitylabelsall models 7ukw, resolution 2.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7ukw is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.6Å Ligands: ZRT Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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. Structural Basis for Inhibition of Mutant EGFR with Lazertinib (YH25448).,Heppner DE, Wittlinger F, Beyett TS, Shaurova T, Urul DA, Buckley B, Pham CD, Schaeffner IK, Yang B, Ogboo BC, May EW, Schaefer EM, Eck MJ, Laufer SA, Hershberger PA ACS Med Chem Lett. 2022 Nov 10;13(12):1856-1863. doi: , 10.1021/acsmedchemlett.2c00213. eCollection 2022 Dec 8. PMID:36518696 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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