5D12

Kinase domain of cSrc in complex with RL40

5D12 の概要

• エントリーDOI: 10.2210/pdb5d12/pdb
• 分子名称: Proto-oncogene tyrosine-protein kinase Src, N-[2-phenyl-4-(1H-pyrazol-3-ylamino)quinazolin-7-yl]prop-2-enamide (2 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); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 66258.36

構造登録者

Becker, C.,Richters, A.,Engel, J.,Rauh, D. (登録日: 2015-08-03, 公開日: 2015-09-09, 最終更新日: 2024-05-08)

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

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

実験手法

X-RAY DIFFRACTION (3 Å)