View source for 7vra


==The crystal structure of EGFR T790M/C797S with the inhibitor HC5476==
<StructureSection load='7vra' size='340' side='right'caption='[[7vra]], [[Resolution|resolution]] 2.41&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7vra]] is a 1 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=7VRA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7VRA 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]] 2.41&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=I0A:25-chloro-11-(ethylsulfonyl)-44-morpholino-11H-5,12-dioxa-3-aza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-benzenacyclododecaphane'>I0A</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=7vra FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7vra OCA], [https://pdbe.org/7vra PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7vra RCSB], [https://www.ebi.ac.uk/pdbsum/7vra PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7vra ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/EGFR_HUMAN EGFR_HUMAN] Defects in EGFR are associated with lung cancer (LNCR) [MIM:[https://omim.org/entry/211980 211980]. LNCR is a common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis.
== Function ==
[https://www.uniprot.org/uniprot/EGFR_HUMAN EGFR_HUMAN] Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TGFA/TGF-alpha, amphiregulin, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF. Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules. May also activate the NF-kappa-B signaling cascade. Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling. Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin.<ref>PMID:7657591</ref> <ref>PMID:11602604</ref> <ref>PMID:12873986</ref> <ref>PMID:10805725</ref> <ref>PMID:11116146</ref> <ref>PMID:11483589</ref> <ref>PMID:17115032</ref> <ref>PMID:21258366</ref> <ref>PMID:12297050</ref> <ref>PMID:12620237</ref> <ref>PMID:15374980</ref> <ref>PMID:19560417</ref> <ref>PMID:20837704</ref>   Isoform 2 may act as an antagonist of EGF action.<ref>PMID:7657591</ref> <ref>PMID:11602604</ref> <ref>PMID:12873986</ref> <ref>PMID:10805725</ref> <ref>PMID:11116146</ref> <ref>PMID:11483589</ref> <ref>PMID:17115032</ref> <ref>PMID:21258366</ref> <ref>PMID:12297050</ref> <ref>PMID:12620237</ref> <ref>PMID:15374980</ref> <ref>PMID:19560417</ref> <ref>PMID:20837704</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Tertiary C797S mutation of epidermal growth factor receptor (EGFR)-mediated resistance in non-small-cell-lung-cancer (NSCLC) patients is still an unmet clinical need. Several classes of adenosine 5'-triphosphate-competitive or allosteric EGFR(T790M/C797S) inhibitors and degraders have been developed, but none of them have received approval from the regulatory agencies. Herein, we report the structure-based design of conformational constrained 4-(1-ethylsufonyl-3-indolyl)-2-phenylaminopyrimidines as new EGFR(T790M/C797S) inhibitors by using a macrocyclization strategy. Representative compound 18j potently inhibited EGFR(19del/T790M/C797S) and EGFR(L858R/T790M/C797S) mutants with IC50 values of 15.8 and 23.6 nM and suppressed Ba/F3-EGFR(L858R/T790M/C797S) and Ba/F3-EGFR(19del/T790M/C797S) cells with IC50 values of 0.036 and 0.052 muM, respectively, which is 10-20-fold more potent than brigatinib. 18j also potently inhibited the EGFR(19del/T790M/C797S)-mutated PC-9-OR NSCLC cell proliferation with an IC50 value of 0.644 muM but was less potent for parental Ba/F3 and A431 cells. This study provides a new lead compound for drug discovery to combat EGFR(C797S)-mediated resistance in NSCLC patients.

Conformational Constrained 4-(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine Derivatives as New Fourth-Generation Epidermal Growth Factor Receptor Inhibitors Targeting T790M/C797S Mutations.,Chen H, Lai M, Zhang T, Chen Y, Tong L, Zhu S, Zhou Y, Ren X, Ding J, Xie H, Lu X, Ding K J Med Chem. 2022 May 12;65(9):6840-6858. doi: 10.1021/acs.jmedchem.2c00168. Epub , 2022 Apr 21. PMID:35446588<ref>PMID:35446588</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7vra" style="background-color:#fffaf0;"></div>

==See Also==
*[[Epidermal growth factor receptor 3D structures|Epidermal growth factor receptor 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Zhu SJ]]