7JXH

HER2 in complex with JBJ-08-178-01

7JXH の概要

• エントリーDOI: 10.2210/pdb7jxh/pdb
• 分子名称: Receptor tyrosine-protein kinase erbB-2, (2E)-N-[3-cyano-7-ethoxy-4-({3-methyl-4-[([1,2,4]triazolo[1,5-a]pyridin-7-yl)oxy]phenyl}amino)quinolin-6-yl]-4-(dimethylamino)but-2-enamide (2 entities in total)
• 機能のキーワード: her2, erbb2, 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: 8
• 化学式量合計: 299577.07

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: 2024-11-13)

主引用文献

Son, J.,Jang, J.,Beyett, T.S.,Eum, Y.,Haikala, H.M.,Verano, A.,Lin, M.,Hatcher, J.M.,Kwiatkowski, N.P.,Eser, P.O.,Poitras, M.J.,Wang, S.,Xu, M.,Gokhale, P.C.,Cameron, M.D.,Eck, M.J.,Gray, N.S.,Janne, P.A.
A Novel HER2-Selective Kinase Inhibitor Is Effective in HER2 Mutant and Amplified Non-Small Cell Lung Cancer.
Cancer Res., 82:1633-1645, 2022

PubMed Abstract: In-frame insertions in exon 20 of HER2 are the most common HER2 mutations in patients with non-small cell lung cancer (NSCLC), a disease in which approved EGFR/HER2 tyrosine kinase inhibitors (TKI) display poor efficiency and undesirable side effects due to their strong inhibition of wild-type (WT) EGFR. Here, we report a HER2-selective covalent TKI, JBJ-08-178-01, that targets multiple HER2 activating mutations, including exon 20 insertions as well as amplification. JBJ-08-178-01 displayed strong selectivity toward HER2 mutants over WT EGFR compared with other EGFR/HER2 TKIs. Determination of the crystal structure of HER2 in complex with JBJ-08-178-01 suggests that an interaction between the inhibitor and Ser783 may be responsible for HER2 selectivity. The compound showed strong antitumoral activity in HER2-mutant or amplified cancers in vitro and in vivo. Treatment with JBJ-08-178-01 also led to a reduction in total HER2 by promoting proteasomal degradation of the receptor. Taken together, the dual activity of JBJ-08-178-01 as a selective inhibitor and destabilizer of HER2 represents a combination that may lead to better efficacy and tolerance in patients with NSCLC harboring HER2 genetic alterations or amplification.

PubMed: 35149586
DOI: 10.1158/0008-5472.CAN-21-2693

実験手法

X-RAY DIFFRACTION (3.27 Å)