7JXQ

EGFR kinase (T790M/V948R) in complex with allosteric inhibitor JBJ-09-063

7JXQ の概要

• エントリーDOI: 10.2210/pdb7jxq/pdb
• 分子名称: Epidermal growth factor receptor, MAGNESIUM ION, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (5 entities in total)
• 機能のキーワード: egfr, erbb1, kinase, inhibitor, transferase, transferase-transferase inhibitor complex, transferase/transferase 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: 155247.00

構造登録者

Beyett, T.S.,Eck, M.J. (登録日: 2020-08-27, 公開日: 2021-09-08, 最終更新日: 2023-10-18)

主引用文献

To, C.,Beyett, T.S.,Jang, J.,Feng, W.W.,Bahcall, M.,Haikala, H.M.,Shin, B.H.,Heppner, D.E.,Rana, J.K.,Leeper, B.A.,Soroko, K.M.,Poitras, M.J.,Gokhale, P.C.,Kobayashi, Y.,Wahid, K.,Kurppa, K.J.,Gero, T.W.,Cameron, M.D.,Ogino, A.,Mushajiang, M.,Xu, C.,Zhang, Y.,Scott, D.A.,Eck, M.J.,Gray, N.S.,Janne, P.A.
An allosteric inhibitor against the therapy-resistant mutant forms of EGFR in non-small cell lung cancer.
Nat Cancer, 3:402-417, 2022

PubMed Abstract: Epidermal growth factor receptor (EGFR) therapy using small-molecule tyrosine kinase inhibitors (TKIs) is initially efficacious in patients with EGFR-mutant lung cancer, although drug resistance eventually develops. Allosteric EGFR inhibitors, which bind to a different EGFR site than existing ATP-competitive EGFR TKIs, have been developed as a strategy to overcome therapy-resistant EGFR mutations. Here we identify and characterize JBJ-09-063, a mutant-selective allosteric EGFR inhibitor that is effective across EGFR TKI-sensitive and resistant models, including those with EGFR T790M and C797S mutations. We further uncover that EGFR homo- or heterodimerization with other ERBB family members, as well as the EGFR L747S mutation, confers resistance to JBJ-09-063, but not to ATP-competitive EGFR TKIs. Overall, our studies highlight the potential clinical utility of JBJ-09-063 as a single agent or in combination with EGFR TKIs to define more effective strategies to treat EGFR-mutant lung cancer.

PubMed: 35422503
DOI: 10.1038/s43018-022-00351-8

実験手法

X-RAY DIFFRACTION (1.83 Å)