8ARJ

Anaplastic Lymphoma Kinase with a novel carboline inhibitor

8ARJ の概要

• エントリーDOI: 10.2210/pdb8arj/pdb
• 分子名称: ALK tyrosine kinase receptor, 3-(dimethylamino)-1-[3-[4-(4-methylpiperazin-1-yl)phenyl]-9~{H}-pyrido[2,3-b]indol-6-yl]prop-2-en-1-one (3 entities in total)
• 機能のキーワード: inhibitor, alk, kinase, antitumor, antitumor protein
• 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: 36461.89

構造登録者

Mologni, L.,Scapozza, L.,Gambacorti-Passerini, C.,Tardy, S.,Goekjian, P.,Robinson, C.,Brown, D. (登録日: 2022-08-17, 公開日: 2022-09-14, 最終更新日: 2024-01-31)

主引用文献

Mologni, L.,Tardy, S.,Zambon, A.,Orsato, A.,Bisson, W.H.,Ceccon, M.,Viltadi, M.,D'Attoma, J.,Pannilunghi, S.,Vece, V.,Bertho, J.,Goekjian, P.,Scapozza, L.,Gambacorti-Passerini, C.
Discovery of Novel alpha-Carboline Inhibitors of the Anaplastic Lymphoma Kinase.
Acs Omega, 7:17083-17097, 2022

PubMed Abstract: The anaplastic lymphoma kinase (ALK) is abnormally expressed and hyperactivated in a number of tumors and represents an ideal therapeutic target. Despite excellent clinical responses to ALK inhibition, drug resistance still represents an issue and novel compounds that overcome drug-resistant mutants are needed. We designed, synthesized, and evaluated a large series of azacarbazole inhibitors. Several lead compounds endowed with submicromolar potency were identified. Compound showed selective inhibition of native and mutant drug-refractory ALK kinase as well as in a Ba/F3 model and in human ALK+ lymphoma cells. The three-dimensional (3D) structure of a :ALK-KD cocrystal is reported, showing extensive interaction through the hinge region and the catalytic lysine 1150.

PubMed: 35647450
DOI: 10.1021/acsomega.2c00507

実験手法

X-RAY DIFFRACTION (1.645 Å)