5hg7

EGFR (L858R, T790M, V948R) in complex with 1-{(3R,4R)-3-[5-Chloro-2-(1-methyl-1H-pyrazol-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxymethyl]-4-methoxy-pyrrolidin-1-yl}propenone (PF-06459988)

Structural highlights 5hg7 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: , Related: 5hg5, 5hg8, 5hg9 Gene: EGFR, ERBB, ERBB1, HER1 (HUMAN) Activity: Receptor protein-tyrosine kinase, with EC number 2.7.10.1 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 First generation EGFR TKIs (gefitinib, erlotinib) provide significant clinical benefit for NSCLC cancer patients with oncogenic EGFR mutations. Ultimately, these patients disease progresses, often driven by a second-site mutation in the EGFR kinase domain (T790M). Another liability of the first generation drugs is severe adverse events driven by inhibition of WT EGFR. As such, our goal was to develop a highly potent irreversible inhibitor with the largest selectivity ratio between the drug-resistant double mutants (L858R/T790M, Del/T790M) and WT EGFR. A unique approach to develop covalent inhibitors, optimization of reversible binding affinity, served as a cornerstone of this effort. PF-06459988, was discovered as a novel, third generation irreversible inhibitor, which demonstrates (i) high potency and specificity to the T790M-containing double mutant EGFRs, (ii) minimal intrinsic chemical reactivity of the electrophilic warhead, (iii) greatly reduced proteome reactivity relative to earlier irreversible EGFR inhibitors and (iv) minimal activity against WT EGFR. Discovery of 1-{(3R,4R)-3-[5-Chloro-2-(1-methyl-1H-pyrazol-4-ylamino)-7H-pyrrolo[2,3-d]pyrimid in-4-yloxymethyl]-4-methoxy-pyrrolidin-1-yl}propenone (PF-06459988), A Potent, WT Sparing, Irreversible Inhibitor of T790M-Containing EGFR Mutants.,Cheng H, Nair SK, Murray BW, Almaden C, Bailey S, Baxi S, Behenna DC, Cho-Schultz S, Dalvie D, Dinh DM, Edwards MP, Feng JL, Ferre R, Gajiwala KS, Hemkens MD, Jackson-Fisher A, Jalaie M, Johnson TO, Kania RS, Kephart S, Lafontaine JA, Lunney E, Liu KK, Liu Z, Matthews J, Nagata A, Niessen S, Ornelas MA, Orr ST, Pairish M, Planken S, Ren S, Richter DT, Ryan K, Sach NW, Shen H, Smeal T, Solowiej J, Sutton SC, Tran K, Tseng E, Vernier WF, Walls M, Wang S, Weinrich SL, Xin S, Xu H, Yin MJ, Zhou R, Zientek M, Kath J J Med Chem. 2016 Jan 12. PMID:26756222 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Epidermal growth factor receptor 3D structures

spinqualitylabelsall models 5hg7, resolution 1.85Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image