4FC0

Crystal Structure of Human Kinase Domain of B-raf with a DFG-out Inhibitor

4FC0 の概要

• エントリーDOI: 10.2210/pdb4fc0/pdb
• 関連するPDBエントリー: 3Q96 4DBN
• 分子名称: Serine/threonine-protein kinase B-raf, 2-chloro-3-[(2-cyanopropan-2-yl)oxy]-N-{5-[{2-[(cyclopropylcarbonyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}(methyl)amino]-2-fluorophenyl}benzamide (3 entities in total)
• 機能のキーワード: human serine/theronine protein kinase, kinase drug complex, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus (By similarity): P15056
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 65802.85

構造登録者

Yano, J.K.,Aertgeerts, K. (登録日: 2012-05-23, 公開日: 2014-01-08, 最終更新日: 2024-02-28)

主引用文献

Hirose, M.,Okaniwa, M.,Miyazaki, T.,Imada, T.,Ohashi, T.,Tanaka, Y.,Arita, T.,Yabuki, M.,Kawamoto, T.,Tsutsumi, S.,Sumita, A.,Takagi, T.,Sang, B.C.,Yano, J.,Aertgeerts, K.,Yoshida, S.,Ishikawa, T.
Design and synthesis of novel DFG-out RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors: 3. Evaluation of 5-amino-linked thiazolo[5,4-d]pyrimidine and thiazolo[5,4-b]pyridine derivatives.
Bioorg.Med.Chem., 20:5600-5615, 2012

PubMed Abstract: Our aim was to discover RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors that possess strong activity and sufficient oral absorption, and thus, we selected a 5-amino-linked thiazolo[5,4-d]pyrimidine derivative as the lead compound because of its potential kinase inhibitory activities and its desired solubility. The novel tertiary 1-cyano-1-methylethoxy substituent was designed to occupy the hydrophobic region of 'back pocket' of BRAF on the basis of the X-ray co-crystal structure data of BRAF. In addition, we found that N-methylation of the amine linker could control the twisted molecular conformation leading to improved solubility. These approaches produced N-methyl thiazolo[5,4-b]pyridine-5-amine derivative 5. To maximize the in vivo efficacy, we attempted salt formation of 5. Our result indicated that the besylate monohydrate salt form (5c) showed significant improvement of both solubility and oral absorption. Owing to the improved physicochemical properties, compound 5c demonstrated regressive antitumor efficacy in a HT-29 xenograft model.

PubMed: 22883026
DOI: 10.1016/j.bmc.2012.07.032

実験手法

X-RAY DIFFRACTION (2.95 Å)