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==Crystal Structure of EGFR T790M/V948R in Complex with Covalent Pyrrolopyrimidine 14d== | ==Crystal Structure of EGFR T790M/V948R in Complex with Covalent Pyrrolopyrimidine 14d== | ||
<StructureSection load='6tfu' size='340' side='right'caption='[[6tfu]]' scene=''> | <StructureSection load='6tfu' size='340' side='right'caption='[[6tfu]], [[Resolution|resolution]] 2.00Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TFU OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TFU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TFU FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=N7K:~{N}-[3-[4-[[1-(phenylmethyl)indazol-5-yl]amino]-7~{H}-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl]propanamide'>N7K</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6tfu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tfu OCA], [https://pdbe.org/6tfu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tfu RCSB], [https://www.ebi.ac.uk/pdbsum/6tfu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tfu ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Mutated or amplified Her2 serves as a driver of non-small cell lung cancer (NSCLC) or mediates resistance toward the inhibition of its family member EGFR (epidermal growth factor receptor) with small-molecule inhibitors. Current data from clinical candidates revealed that inhibitors targeting Her2 suffer from poor response rates of less than 40%, and therefore, the development of novel inhibitors was undertaken. In this study, the well-established pyrrolopyrimidine scaffold was modified with structural motifs identified from a screening campaign with more than 1600 compounds which were applied against wild-type Her2 and its mutant variant Her2-A775_G776insYVMA. The resulting inhibitors were designed to covalently target a reactive cysteine in the binding site of Her2 and were further optimized by means of structure-based drug design utilizing a set of obtained complex crystal structures. In addition, the analysis of binding kinetics and absorption, distribution, metabolism, and excretion (ADME) parameters, as well as MS experiments and western blot analysis substantiated our approach. | |||
Targeting Her2-insYVMA with Covalent Inhibitors - A Focused Compound Screening and Structure-Based Design Approach.,Lategahn J, Hardick J, Grabe T, Niggenaber J, Jeyakumar K, Keul M, Tumbrink HL, Becker C, Hodson L, Kirschner T, Klovekorn P, Ketzer J, Baumann M, Terheyden S, Unger A, Weisner J, Muller MP, van Otterlo WAL, Bauer S, Rauh D J Med Chem. 2020 Sep 15. doi: 10.1021/acs.jmedchem.0c00870. PMID:32931277<ref>PMID:32931277</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6tfu" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Epidermal growth factor receptor 3D structures|Epidermal growth factor receptor 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Latest revision as of 11:21, 17 October 2024
Crystal Structure of EGFR T790M/V948R in Complex with Covalent Pyrrolopyrimidine 14dCrystal Structure of EGFR T790M/V948R in Complex with Covalent Pyrrolopyrimidine 14d
Structural highlights
Publication Abstract from PubMedMutated or amplified Her2 serves as a driver of non-small cell lung cancer (NSCLC) or mediates resistance toward the inhibition of its family member EGFR (epidermal growth factor receptor) with small-molecule inhibitors. Current data from clinical candidates revealed that inhibitors targeting Her2 suffer from poor response rates of less than 40%, and therefore, the development of novel inhibitors was undertaken. In this study, the well-established pyrrolopyrimidine scaffold was modified with structural motifs identified from a screening campaign with more than 1600 compounds which were applied against wild-type Her2 and its mutant variant Her2-A775_G776insYVMA. The resulting inhibitors were designed to covalently target a reactive cysteine in the binding site of Her2 and were further optimized by means of structure-based drug design utilizing a set of obtained complex crystal structures. In addition, the analysis of binding kinetics and absorption, distribution, metabolism, and excretion (ADME) parameters, as well as MS experiments and western blot analysis substantiated our approach. Targeting Her2-insYVMA with Covalent Inhibitors - A Focused Compound Screening and Structure-Based Design Approach.,Lategahn J, Hardick J, Grabe T, Niggenaber J, Jeyakumar K, Keul M, Tumbrink HL, Becker C, Hodson L, Kirschner T, Klovekorn P, Ketzer J, Baumann M, Terheyden S, Unger A, Weisner J, Muller MP, van Otterlo WAL, Bauer S, Rauh D J Med Chem. 2020 Sep 15. doi: 10.1021/acs.jmedchem.0c00870. PMID:32931277[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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