8wd4

EGFR(L858R/T790/C797S) in complex with compound 5j

spinqualitylabelsall models 8wd4, resolution 2.55Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8wd4 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 2.55Å Ligands: CL, W7W 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 The C797S mutation is one of the major factors behind resistance to the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Herein, we describe the discovery of the 2,4-diaminonicotinamide derivative 5j, which shows potent inhibitory activity against EGFR del19/T790M/C797S and L858R/T790M/C797S. We also report the structure-activity relationship of the 2,4-diaminonicotinamide derivatives and the co-crystal structure of 5j and EGFR del19/T790M/C797S. Synthesis, activity, and their relationships of 2,4-diaminonicotinamide derivatives as EGFR inhibitors targeting C797S mutation.,Kageji H, Momose T, Nagamoto Y, Togashi N, Yasumatsu I, Nishikawa Y, Kihara K, Hiramoto K, Minami M, Kasanuki N, Isoyama T, Naito H Bioorg Med Chem Lett. 2023 Dec 6:129575. doi: 10.1016/j.bmcl.2023.129575. PMID:38065292 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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