7LGS

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

Summary for 7LGS

• Entry DOI: 10.2210/pdb7lgs/pdb
• Descriptor: 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)
• Functional Keywords: kinase, inhibitor, covalent, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 153321.10

Authors

Skene, R.J.,Lane, W. (deposition date: 2021-01-21, release date: 2021-09-22, Last modification date: 2024-11-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3.1 Å)