5HG5

EGFR (L858R, T790M, V948R) in complex with N-{3-[(2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]phenyl}prop-2-enamide

5HG5 の概要

• エントリーDOI: 10.2210/pdb5hg5/pdb
• 関連するPDBエントリー: 5HG7 5HG8 5HG9
• 分子名称: Epidermal growth factor receptor, N-{3-[(2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]phenyl}propanamide, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: egfr, inhibitor, complex, lung cancer, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted: P00533
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 38240.16

構造登録者

Gajiwala, K.S. (登録日: 2016-01-08, 公開日: 2016-02-03, 最終更新日: 2024-10-30)

主引用文献

Cheng, H.,Nair, S.K.,Murray, B.W.,Almaden, C.,Bailey, S.,Baxi, S.,Behenna, D.,Cho-Schultz, S.,Dalvie, D.,Dinh, D.M.,Edwards, M.P.,Feng, J.L.,Ferre, R.A.,Gajiwala, K.S.,Hemkens, M.D.,Jackson-Fisher, A.,Jalaie, M.,Johnson, T.O.,Kania, R.S.,Kephart, S.,Lafontaine, J.,Lunney, B.,Liu, K.K.,Liu, Z.,Matthews, J.,Nagata, A.,Niessen, S.,Ornelas, M.A.,Orr, S.T.,Pairish, M.,Planken, S.,Ren, S.,Richter, D.,Ryan, K.,Sach, N.,Shen, H.,Smeal, T.,Solowiej, J.,Sutton, S.,Tran, K.,Tseng, E.,Vernier, W.,Walls, M.,Wang, S.,Weinrich, S.L.,Xin, S.,Xu, H.,Yin, M.J.,Zientek, M.,Zhou, R.,Kath, J.C.
Discovery of 1-{(3R,4R)-3-[({5-Chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]-4-methoxypyrrolidin-1-yl}prop-2-en-1-one (PF-06459988), a Potent, WT Sparing, Irreversible Inhibitor of T790M-Containing EGFR Mutants.
J.Med.Chem., 59:2005-2024, 2016

PubMed Abstract: 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.

PubMed: 26756222
DOI: 10.1021/acs.jmedchem.5b01633

実験手法

X-RAY DIFFRACTION (1.52 Å)