6S8A

Crystal Structure of EGFR-T790M/C797S in Complex with Covalent Pyrrolopyrimidine 19h

6S8A の概要

• エントリーDOI: 10.2210/pdb6s8a/pdb
• 分子名称: Epidermal growth factor receptor, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ~{N}-[3-[6-[4-(4-methylpiperazin-1-yl)phenyl]-4-(2-methylpropoxy)-7~{H}-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl]propanamide, ... (4 entities in total)
• 機能のキーワード: egfr, t790m/c797s, covalent pyrrolopyrimide, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 38423.50

構造登録者

Niggenaber, J.,Mueller, M.P.,Rauh, D. (登録日: 2019-07-09, 公開日: 2019-10-16, 最終更新日: 2024-01-24)

主引用文献

Lategahn, J.,Keul, M.,Klovekorn, P.,Tumbrink, H.L.,Niggenaber, J.,Muller, M.P.,Hodson, L.,Flasshoff, M.,Hardick, J.,Grabe, T.,Engel, J.,Schultz-Fademrecht, C.,Baumann, M.,Ketzer, J.,Muhlenberg, T.,Hiller, W.,Gunther, G.,Unger, A.,Muller, H.,Heimsoeth, A.,Golz, C.,Blank-Landeshammer, B.,Kollipara, L.,Zahedi, R.P.,Strohmann, C.,Hengstler, J.G.,van Otterlo, W.A.L.,Bauer, S.,Rauh, D.
Inhibition of osimertinib-resistant epidermal growth factor receptor EGFR-T790M/C797S.
Chem Sci, 10:10789-10801, 2019

PubMed Abstract: Precision medicine has revolutionized the treatment of patients in EGFR driven non-small cell lung cancer (NSCLC). Targeted drugs show high response rates in genetically defined subsets of cancer patients and markedly increase their progression-free survival as compared to conventional chemotherapy. However, recurrent acquired drug resistance limits the success of targeted drugs in long-term treatment and requires the constant development of novel efficient inhibitors of drug resistant cancer subtypes. Herein, we present covalent inhibitors of the drug resistant gatekeeper mutant EGFR-L858R/T790M based on the pyrrolopyrimidine scaffold. Biochemical and cellular characterization, as well as kinase selectivity profiling and western blot analysis, substantiate our approach. Moreover, the developed compounds possess high activity against multi drug resistant EGFR-L858R/T790M/C797S in biochemical assays due to their highly reversible binding character, that was revealed by characterization of the binding kinetics. In addition, we present the first X-ray crystal structures of covalent inhibitors in complex with C797S-mutated EGFR which provide detailed insight into their binding mode.

PubMed: 31857889
DOI: 10.1039/c9sc03445e

実験手法

X-RAY DIFFRACTION (2.6 Å)