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5D10

Kinase domain of cSrc in complex with RL236

5D10 の概要
エントリーDOI10.2210/pdb5d10/pdb
分子名称Proto-oncogene tyrosine-protein kinase Src, N-[4-({4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}oxy)phenyl]prop-2-enamide (3 entities in total)
機能のキーワードkinase inhibitor, drug resistance, transferase
由来する生物種Gallus gallus (Chicken)
細胞内の位置Cell membrane : P00523
タンパク質・核酸の鎖数2
化学式量合計66414.59
構造登録者
Becker, C.,Mayer-Wrangowski, S.C.,Julian, E.,Rauh, D. (登録日: 2015-08-03, 公開日: 2015-09-02, 最終更新日: 2024-01-10)
主引用文献Engel, J.,Richters, A.,Getlik, M.,Tomassi, S.,Keul, M.,Termathe, M.,Lategahn, J.,Becker, C.,Mayer-Wrangowski, S.,Grutter, C.,Uhlenbrock, N.,Krull, J.,Schaumann, N.,Eppmann, S.,Kibies, P.,Hoffgaard, F.,Heil, J.,Menninger, S.,Ortiz-Cuaran, S.,Heuckmann, J.M.,Tinnefeld, V.,Zahedi, R.P.,Sos, M.L.,Schultz-Fademrecht, C.,Thomas, R.K.,Kast, S.M.,Rauh, D.
Targeting Drug Resistance in EGFR with Covalent Inhibitors: A Structure-Based Design Approach.
J.Med.Chem., 58:6844-6863, 2015
Cited by
PubMed Abstract: Receptor tyrosine kinases represent one of the prime targets in cancer therapy, as the dysregulation of these elementary transducers of extracellular signals, like the epidermal growth factor receptor (EGFR), contributes to the onset of cancer, such as non-small cell lung cancer (NSCLC). Strong efforts were directed to the development of irreversible inhibitors and led to compound CO-1686, which takes advantage of increased residence time at EGFR by alkylating Cys797 and thereby preventing toxic effects. Here, we present a structure-based approach, rationalized by subsequent computational analysis of conformational ligand ensembles in solution, to design novel and irreversible EGFR inhibitors based on a screening hit that was identified in a phenotype screen of 80 NSCLC cell lines against approximately 1500 compounds. Using protein X-ray crystallography, we deciphered the binding mode in engineered cSrc (T338M/S345C), a validated model system for EGFR-T790M, which constituted the basis for further rational design approaches. Chemical synthesis led to further compound collections that revealed increased biochemical potency and, in part, selectivity toward mutated (L858R and L858R/T790M) vs nonmutated EGFR. Further cell-based and kinetic studies were performed to substantiate our initial findings. Utilizing proteolytic digestion and nano-LC-MS/MS analysis, we confirmed the alkylation of Cys797.
PubMed: 26275028
DOI: 10.1021/acs.jmedchem.5b01082
主引用文献が同じPDBエントリー
実験手法
X-RAY DIFFRACTION (2.7 Å)
構造検証レポート
Validation report summary of 5d10
検証レポート(詳細版)ダウンロードをダウンロード

227561

件を2024-11-20に公開中

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