8a2d | pdb_00008a2d

EGFR kinase domain (L858R/V948R) in complex with 2-[4-(difluoromethyl)-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-7-methyl-indazol-2-yl]-2-spiro[6,7-dihydropyrrolo[1,2-c]imidazole-5,1'-cyclopropane]-1-yl-N-thiazol-2-yl-acetamide

spinqualitylabelsall models 8a2d, resolution 1.11Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8a2d is a 1 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 1.11Å Ligands: EDO, KXY, MES Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease EGFR_HUMAN Defects in EGFR are associated with lung cancer (LNCR) [MIM: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 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. Isoform 2 may act as an antagonist of EGF action. Publication Abstract from PubMed Addressing resistance to third-generation EGFR TKIs such as osimertinib via the EGFR(C797S) mutation remains a highly unmet need in EGFR-driven non-small-cell lung cancer (NSCLC). Herein, we present the discovery of the allosteric EGFR inhibitor 57, a novel fourth-generation inhibitor to overcome EGFR(C797S)-mediated resistance in patients harboring the activating EGFR(L858R) mutation. 57 exhibits an improved potency compared to previous allosteric EGFR inhibitors. To our knowledge, 57 is the first allosteric EGFR inhibitor that demonstrates robust tumor regression in a mutant EGFR(L858R/C797S) tumor model. Additionally, 57 is active in an H1975 EGFR(L858R/T790M) NSCLC xenograft model and shows superior efficacy in combination with osimertinib compared to the single agents. Our data highlight the potential of 57 as a single agent against EGFR(L858R/C797S) and EGFR(L858R/T790M/C797S) and as combination therapy for EGFR(L858R)- and EGFR(L858R/T790M)-driven NSCLC. Discovery of Novel Allosteric EGFR L858R Inhibitors for the Treatment of Non-Small-Cell Lung Cancer as a Single Agent or in Combination with Osimertinib.,Obst-Sander U, Ricci A, Kuhn B, Friess T, Koldewey P, Kuglstatter A, Hewings D, Goergler A, Steiner S, Rueher D, Imhoff MP, Raschetti N, Marty HP, Dietzig A, Rynn C, Ehler A, Burger D, Kornacker M, Schaffland JP, Herting F, Pao W, Bischoff JR, Martoglio B, Alice Nagel Y, Jaeschke G J Med Chem. 2022 Oct 13;65(19):13052-13073. doi: 10.1021/acs.jmedchem.2c00893., Epub 2022 Sep 30. PMID:36178776 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Epidermal growth factor receptor 3D structures

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