3EFJ

Structure of c-Met with pyrimidone inhibitor 7

3EFJ の概要

• エントリーDOI: 10.2210/pdb3efj/pdb
• 関連するPDBエントリー: 3EFK
• 分子名称: Hepatocyte growth factor receptor, 2-benzyl-5-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]-3-fluorophenyl}-3-methylpyrimidin-4(3H)-one (3 entities in total)
• 機能のキーワード: c-met, alternative splicing, atp-binding, chromosomal rearrangement, disease mutation, glycoprotein, kinase, membrane, nucleotide-binding, phosphoprotein, polymorphism, proto-oncogene, receptor, transferase, transmembrane, tyrosine-protein kinase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein: P08581
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 71688.85

構造登録者

D'Angelo, N.,Bellon, S.,Whittington, D. (登録日: 2008-09-09, 公開日: 2008-10-07, 最終更新日: 2023-08-30)

主引用文献

D'Angelo, N.D.,Bellon, S.F.,Booker, S.K.,Cheng, Y.,Coxon, A.,Dominguez, C.,Fellows, I.,Hoffman, D.,Hungate, R.,Kaplan-Lefko, P.,Lee, M.R.,Li, C.,Liu, L.,Rainbeau, E.,Reider, P.J.,Rex, K.,Siegmund, A.,Sun, Y.,Tasker, A.S.,Xi, N.,Xu, S.,Yang, Y.,Zhang, Y.,Burgess, T.L.,Dussault, I.,Kim, T.S.
Design, synthesis, and biological evaluation of potent c-Met inhibitors.
J.Med.Chem., 51:5766-5779, 2008

PubMed Abstract: c-Met is a receptor tyrosine kinase that plays a key role in several cellular processes but has also been found to be overexpressed and mutated in different human cancers. Consequently, targeting this enzyme has become an area of intense research in drug discovery. Our studies began with the design and synthesis of novel pyrimidone 7, which was found to be a potent c-Met inhibitor. Subsequent SAR studies identified 22 as a more potent analog, whereas an X-ray crystal structure of 7 bound to c-Met revealed an unexpected binding conformation. This latter finding led to the development of a new series that featured compounds that were more potent both in vitro and in vivo than 22 and also exhibited different binding conformations to c-Met. Novel c-Met inhibitors have been designed, developed, and found to be potent in vitro and in vivo.

PubMed: 18763753
DOI: 10.1021/jm8006189

実験手法

X-RAY DIFFRACTION (2.6 Å)