7A2A

Crystal Structure of EGFR-T790M/V948R in Complex with Spebrutinib and EAI001

7A2A の概要

• エントリーDOI: 10.2210/pdb7a2a/pdb
• 分子名称: Epidermal growth factor receptor, (2R)-2-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2-phenyl-N-(1,3-thiazol-2-yl)acetamide, ~{N}-[3-[[5-fluoranyl-2-[[4-(2-methoxyethoxy)phenyl]amino]pyrimidin-4-yl]amino]phenyl]propanamide, ... (6 entities in total)
• 機能のキーワード: egfr, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 77897.25

構造登録者

Niggenaber, J.,Mueller, M.P.,Rauh, D. (登録日: 2020-08-17, 公開日: 2020-11-11, 最終更新日: 2024-11-06)

主引用文献

Niggenaber, J.,Heyden, L.,Grabe, T.,Muller, M.P.,Lategahn, J.,Rauh, D.
Complex Crystal Structures of EGFR with Third-Generation Kinase Inhibitors and Simultaneously Bound Allosteric Ligands.
Acs Med.Chem.Lett., 11:2484-2490, 2020

PubMed Abstract: Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) and currently the gold-standard for the treatment of patients suffering from non-small cell lung cancer (NSCLC) harboring T790M-mutated epidermal growth factor receptor (EGFR). The outcome of the treatment, however, is limited by the emergence of the C797S resistance mutation. Allosteric inhibitors have a different mode of action and were developed to overcome this limitation. However, most of these innovative molecules are not effective as a single agent. Recently, mutated EGFR was successfully addressed with osimertinib combined with the allosteric inhibitor JBJ-04-125-02, but surprisingly, structural insights into their binding mode were lacking. Here, we present the first complex crystal structures of mutant EGFR in complex with third-generation inhibitors such as osimertinib and mavelertinib in the presence of simultaneously bound allosteric inhibitors. These structures highlight the possibility of further combinations targeting EGFR and lay the foundation for hybrid inhibitors as next-generation TKIs.

PubMed: 33335671
DOI: 10.1021/acsmedchemlett.0c00472

実験手法

X-RAY DIFFRACTION (1.9 Å)