5hg9

EGFR (L858R, T790M, V948R) in complex with 1-[(3R,4R)-3-[({2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]-4-(trifluoromethyl)pyrrolidin-1-yl]prop-2-en-1-oneEGFR (L858R, T790M, V948R) in complex with 1-[(3R,4R)-3-[({2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]-4-(trifluoromethyl)pyrrolidin-1-yl]prop-2-en-1-one

Structural highlights 5hg9 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 2.15Å Ligands: , , Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 5hg9, resolution 2.15Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image