6N3O

Identification of novel, potent and selective GCN2 inhibitors as first-in-class anti-tumor agents

6N3O の概要

• エントリーDOI: 10.2210/pdb6n3o/pdb
• 分子名称: eIF-2-alpha kinase GCN2, N-{3-[(2-aminopyrimidin-5-yl)ethynyl]-2,4-difluorophenyl}-5-chloro-2-methoxypyridine-3-sulfonamide (3 entities in total)
• 機能のキーワード: gcn2, kinase, inhibitor, anti-tumor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36663.61

構造登録者

Hoffman, I.D.,Fujimoto, J.,Kurasawa, O.,Takagi, T.,Klein, M.G.,Kefala, G.,Ding, S.C.,Cary, D.R.,Mizojiri, R. (登録日: 2018-11-15, 公開日: 2019-10-09, 最終更新日: 2024-03-13)

主引用文献

Fujimoto, J.,Kurasawa, O.,Takagi, T.,Liu, X.,Banno, H.,Kojima, T.,Asano, Y.,Nakamura, A.,Nambu, T.,Hata, A.,Ishii, T.,Sameshima, T.,Debori, Y.,Miyamoto, M.,Klein, M.G.,Tjhen, R.,Sang, B.C.,Levin, I.,Lane, S.W.,Snell, G.P.,Li, K.,Kefala, G.,Hoffman, I.D.,Ding, S.C.,Cary, D.R.,Mizojiri, R.
Identification of Novel, Potent, and Orally Available GCN2 Inhibitors with Type I Half Binding Mode.
Acs Med.Chem.Lett., 10:1498-1503, 2019

PubMed Abstract: General control nonderepressible 2 (GCN2) is a master regulator kinase of amino acid homeostasis and important for cancer survival in the tumor microenvironment under amino acid depletion. We initiated studies aiming at the discovery of novel GCN2 inhibitors as first-in-class antitumor agents and conducted modification of the substructure of sulfonamide derivatives with expected type I half binding on GCN2. Our synthetic strategy mainly corresponding to the αC-helix allosteric pocket of GCN2 led to significant enhancement in potency and a good pharmacokinetic profile in mice. In addition, compound , which showed slow dissociation in binding on GCN2, demonstrated antiproliferative activity in combination with the asparagine-depleting agent asparaginase in an acute lymphoblastic leukemia (ALL) cell line, and it also displayed suppression of GCN2 pathway activation with asparaginase treatment in the ALL cell line and mouse xenograft model.

PubMed: 31620240
DOI: 10.1021/acsmedchemlett.9b00400

実験手法

X-RAY DIFFRACTION (2.4 Å)