6MX8

Crystal structure of anaplastic lymphoma kinase (ALK) bound by Brigatinib

「5J7H」から置き換えられました

6MX8 の概要

• エントリーDOI: 10.2210/pdb6mx8/pdb
• 分子名称: ALK tyrosine kinase receptor, 5-chloro-N~4~-[2-(dimethylphosphoryl)phenyl]-N~2~-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine (3 entities in total)
• 機能のキーワード: alk kinase, brigatinib, tyrosine kinase, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35073.80

構造登録者

Dougan, D.R.,Zhou, T. (登録日: 2018-10-30, 公開日: 2018-12-12, 最終更新日: 2024-03-13)

主引用文献

Huang, W.S.,Liu, S.,Zou, D.,Thomas, M.,Wang, Y.,Zhou, T.,Romero, J.,Kohlmann, A.,Li, F.,Qi, J.,Cai, L.,Dwight, T.A.,Xu, Y.,Xu, R.,Dodd, R.,Toms, A.,Parillon, L.,Lu, X.,Anjum, R.,Zhang, S.,Wang, F.,Keats, J.,Wardwell, S.D.,Ning, Y.,Xu, Q.,Moran, L.E.,Mohemmad, Q.K.,Jang, H.G.,Clackson, T.,Narasimhan, N.I.,Rivera, V.M.,Zhu, X.,Dalgarno, D.,Shakespeare, W.C.
Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase.
J. Med. Chem., 59:4948-4964, 2016

PubMed Abstract: In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC50s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.

PubMed: 27144831
DOI: 10.1021/acs.jmedchem.6b00306

実験手法

X-RAY DIFFRACTION (1.96 Å)