9os6

Canertinib (CI-1033) in complex with wild-type EGFR

spinqualitylabelsall models 9os6, resolution 2.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9os6 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 2.75Å Ligands: A1CEA 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 Targeted covalent inhibitors (TCIs) are actively pursued in drug discovery due to their prolonged target engagement and clinical efficacy. Although kinetic parameters provide a path to their optimization, systematic design strategies and practical guidance remain underexplored. In this study, the EGFR kinase is deployed as a model system to elucidate structural and functional determinants critical for directing the optimization of irreversible TCIs. Functional analyses reveal a two-phase optimization process, underscoring the importance of balancing horizontal line rather than maximizing horizontal line the inactivation efficiency rate (k(inact)/K(I)). Selective inhibition of the oncogenic L858R/T790M mutant over the wild-type is achieved by tuning this balance, particularly for TCIs exhibiting the fastest k(inact)/K(I). Structural studies indicate that certain hydrophobic and hydrophilic interactions are associated with L858R/T790M selectivity, offering insights into structure-guided design. These results offer a broadly applicable approach for prioritizing compounds and support the integration of kinetic and selectivity data in TCI discovery campaigns. Profiling and Optimizing Targeted Covalent Inhibitors through EGFR-Guided Studies.,Damghani T, Chitnis SP, Abidakun OA, Patel KB, Lin KS, Ouellette EA, Lantry AM, Heppner DE J Med Chem. 2025 Aug 28;68(16):17917-17932. doi: 10.1021/acs.jmedchem.5c01661. , Epub 2025 Aug 13. PMID:40801664 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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