5UWD

Crystal structure of EGFR kinase domain (L858R, T790M, V948R) in complex with the covalent inhibitor CO-1686

5UWD の概要

• エントリーDOI: 10.2210/pdb5uwd/pdb
• 関連するPDBエントリー: 5UGC
• 分子名称: Epidermal growth factor receptor, N-(3-{[2-{[4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl]amino}phenyl)propanamide (2 entities in total)
• 機能のキーワード: egfr, kinase, covalent inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted: P00533
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 38138.02

構造登録者

Gajiwala, K.S.,Ferre, R.A. (登録日: 2017-02-21, 公開日: 2017-10-18, 最終更新日: 2024-10-16)

主引用文献

Niessen, S.,Dix, M.M.,Barbas, S.,Potter, Z.E.,Lu, S.,Brodsky, O.,Planken, S.,Behenna, D.,Almaden, C.,Gajiwala, K.S.,Ryan, K.,Ferre, R.,Lazear, M.R.,Hayward, M.M.,Kath, J.C.,Cravatt, B.F.
Proteome-wide Map of Targets of T790M-EGFR-Directed Covalent Inhibitors.
Cell Chem Biol, 24:1388-1400.e7, 2017

PubMed Abstract: Patients with non-small cell lung cancers that have kinase-activating epidermal growth factor receptor (EGFR) mutations are highly responsive to first- and second-generation EGFR inhibitors. However, these patients often relapse due to a secondary, drug-resistant mutation in EGFR whereby the gatekeeper threonine is converted to methionine (T790M). Several third-generation EGFR inhibitors have been developed that irreversibly inactivate T790M-EGFR while sparing wild-type EGFR, thus reducing epithelium-based toxicities. Using chemical proteomics, we show here that individual T790M-EGFR inhibitors exhibit strikingly distinct off-target profiles in human cells. The FDA-approved drug osimertinib (AZD9291), in particular, was found to covalently modify cathepsins in cell and animal models, which correlated with lysosomal accumulation of the drug. Our findings thus show how chemical proteomics can be used to differentiate covalent kinase inhibitors based on global selectivity profiles in living systems and identify specific off-targets of these inhibitors that may affect drug activity and safety.

PubMed: 28965727
DOI: 10.1016/j.chembiol.2017.08.017

実験手法

X-RAY DIFFRACTION (3.06 Å)