View source for 7ukw


==EGFR(T790M/V948R) in complex with Lazertinib (YH25448)==
<StructureSection load='7ukw' size='340' side='right'caption='[[7ukw]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7ukw]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7UKW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UKW FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZRT:N-[5-{[(4P)-4-{4-[(dimethylamino)methyl]-3-phenyl-1H-pyrazol-1-yl}pyrimidin-2-yl]amino}-4-methoxy-2-(morpholin-4-yl)phenyl]propanamide'>ZRT</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7ukw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ukw OCA], [https://pdbe.org/7ukw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ukw RCSB], [https://www.ebi.ac.uk/pdbsum/7ukw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ukw ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== 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<ref>PMID:36518696</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7ukw" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Heppner DE]]
[[Category: Pham CD]]