7LGS

Structure of EGFR_D770_N771insNPG/V948R in complex with covalent inhibitor Osimertinib.

7LGS の概要

• エントリーDOI: 10.2210/pdb7lgs/pdb
• 分子名称: Epidermal growth factor receptor, ~{N}-[2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]propanamide, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: kinase, inhibitor, covalent, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 153321.10

構造登録者

Skene, R.J.,Lane, W. (登録日: 2021-01-21, 公開日: 2021-09-22, 最終更新日: 2024-11-20)

主引用文献

Gonzalvez, F.,Vincent, S.,Baker, T.E.,Gould, A.E.,Li, S.,Wardwell, S.D.,Nadworny, S.,Ning, Y.,Zhang, S.,Huang, W.S.,Hu, Y.,Li, F.,Greenfield, M.T.,Zech, S.G.,Das, B.,Narasimhan, N.I.,Clackson, T.,Dalgarno, D.,Shakespeare, W.C.,Fitzgerald, M.,Chouitar, J.,Griffin, R.J.,Liu, S.,Wong, K.K.,Zhu, X.,Rivera, V.M.
Mobocertinib (TAK-788): A Targeted Inhibitor of EGFR Exon 20 Insertion Mutants in Non-Small Cell Lung Cancer.
Cancer Discov, 11:1672-1687, 2021

PubMed Abstract: Most exon 20 insertion (ex20ins) driver mutations in non-small cell lung cancer (NSCLC) are insensitive to approved EGFR tyrosine kinase inhibitors (TKI). To address the limitations of existing therapies targeting -mutated NSCLC, mobocertinib (TAK-788), a novel irreversible EGFR TKI, was specifically designed to potently inhibit oncogenic variants containing activating ex20ins mutations with selectivity over wild-type EGFR. The and activity of mobocertinib was evaluated in engineered and patient-derived models harboring diverse ex20ins mutations. Mobocertinib inhibited viability of various EGFRex20ins-driven cell lines more potently than approved EGFR TKIs and demonstrated antitumor efficacy in patient-derived xenografts and murine orthotopic models. These findings support the ongoing clinical development of mobocertinib for the treatment of ex20ins-mutated NSCLC. SIGNIFICANCE: No oral EGFR-targeted therapies are approved for exon 20 insertion (ex20ins) mutation-driven NSCLC. Mobocertinib is a novel small-molecule EGFR inhibitor specifically designed to target EGFRex20ins mutants. Preclinical data reported here support the clinical development of mobocertinib in patients with NSCLC with exon 20 insertion mutations...

PubMed: 33632773
DOI: 10.1158/2159-8290.CD-20-1683

実験手法

X-RAY DIFFRACTION (3.1 Å)