4Z55

Anaplastic lymphoma kinase catalytic domain complexed with pyrazolopyrimidine derivative of LDK378

4Z55 の概要

• エントリーDOI: 10.2210/pdb4z55/pdb
• 関連するPDBエントリー: 3L9P 3LCS 3LCT 4MKC
• 分子名称: ALK tyrosine kinase receptor, GLYCEROL, N~6~-[5-methyl-4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]-N~4~-[2-(propan-2-ylsulfonyl)phenyl]-2H-pyrazolo[3,4-d]pyrimidine-4,6-diamine, ... (4 entities in total)
• 機能のキーワード: catalytic domain, transferase, 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 : Q9UM73
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 38999.80

構造登録者

Lee, C.C.,Spraggon, G. (登録日: 2015-04-02, 公開日: 2016-02-03, 最終更新日: 2024-03-06)

主引用文献

Michellys, P.Y.,Chen, B.,Jiang, T.,Jin, Y.,Lu, W.,Marsilje, T.H.,Pei, W.,Uno, T.,Zhu, X.,Wu, B.,Nguyen, T.N.,Bursulaya, B.,Lee, C.,Li, N.,Kim, S.,Tuntland, T.,Liu, B.,Sun, F.,Steffy, A.,Hood, T.
Design and synthesis of novel selective anaplastic lymphoma kinase inhibitors.
Bioorg.Med.Chem.Lett., 26:1090-1096, 2016

PubMed Abstract: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase belonging to the insulin receptor superfamily. Expression of ALK in normal human tissues is only found in a subset of neural cells, however it is involved in the genesis of several cancers through genetic aberrations involving translocation of the kinase domain with multiple fusion partners (e.g., NPM-ALK in anaplastic large cell lymphoma ALCL or EML4-ALK in non-small cell lung cancer) or activating mutations in the full-length receptor resulting in ligand-independent constitutive activation (e.g., neuroblastoma). Here we are reporting the discovery of novel and selective anaplastic lymphoma kinase inhibitors from specific modifications of the 2,4-diaminopyridine core present in TAE684 and LDK378. Synthesis, structure activity relationships (SAR), absorption, distribution, metabolism, and excretion (ADME) profile, and in vivo efficacy in a mouse xenograft model of anaplastic large cell lymphoma are described.

PubMed: 26750252
DOI: 10.1016/j.bmcl.2015.11.049

実験手法

X-RAY DIFFRACTION (1.55 Å)