3U6J

Crystal structure of the VEGFR2 kinase domain in complex with a pyrazolone inhibitor

3U6J の概要

• エントリーDOI: 10.2210/pdb3u6j/pdb
• 関連するPDBエントリー: 3U6H 3U6I
• 分子名称: Vascular endothelial growth factor receptor 2, N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]-3-fluorophenyl}-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (3 entities in total)
• 機能のキーワード: kdr, flk-1, angiogenesis, phosphotransferase, cancer, vascular endothelial growth factor, transferase/transferase inhibitor, transferase-transferase inhibitor complex
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Isoform 1: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted (Probable). Isoform 3: Secreted: P35968
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36685.23

構造登録者

Whittington, D.A.,Long, A.,Rose, P.,Gu, Y.,Zhao, H. (登録日: 2011-10-12, 公開日: 2012-02-22, 最終更新日: 2024-02-28)

主引用文献

Norman, M.H.,Liu, L.,Lee, M.,Xi, N.,Fellows, I.,D'Angelo, N.D.,Dominguez, C.,Rex, K.,Bellon, S.F.,Kim, T.S.,Dussault, I.
Structure-based design of novel class II c-Met inhibitors: 1. Identification of pyrazolone-based derivatives.
J.Med.Chem., 55:1858-1867, 2012

PubMed Abstract: Deregulation of c-Met receptor tyrosine kinase activity leads to tumorigenesis and metastasis in animal models. More importantly, the identification of activating mutations in c-Met, as well as MET gene amplification in human cancers, points to c-Met as an important target for cancer therapy. We have previously described two classes of c-Met kinase inhibitors (class I and class II) that differ in their binding modes and selectivity profiles. The class II inhibitors tend to have activities on multiple kinases. Knowledge of the binding mode of these molecules in the c-Met protein led to the design and evaluation of several new class II c-Met inhibitors that utilize various 5-membered cyclic carboxamides to conformationally restrain key pharmacophoric groups within the molecule. These investigations resulted in the identification of a potent and novel class of pyrazolone c-Met inhibitors with good in vivo activity.

PubMed: 22320343
DOI: 10.1021/jm201330u

実験手法

X-RAY DIFFRACTION (2.15 Å)