3WHA

Hsp90 alpha N-terminal domain in complex with a tricyclic inhibitor

3WHA の概要

• エントリーDOI: 10.2210/pdb3wha/pdb
• 関連するPDBエントリー: 3B28
• 分子名称: Heat shock protein HSP 90-alpha, GLYCEROL, 4-{[4-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-1,3,5-triazin-2-yl]sulfanyl}butanamide, ... (5 entities in total)
• 機能のキーワード: chaperone, chaperone-chaperone inhibitor complex, chaperone/chaperone inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P07900
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 52524.12

構造登録者

Fukami, T.A.,Ono, N. (登録日: 2013-08-23, 公開日: 2014-01-29, 最終更新日: 2023-11-08)

主引用文献

Suda, A.,Kawasaki, K.,Komiyama, S.,Isshiki, Y.,Yoon, D.-O.,Kim, S.-J.,Na, Y.-J.,Hasegawa, K.,Fukami, T.A.,Sato, S.,Miura, T.,Ono, N.,Yamazaki, T.,Saitoh, R.,Shimma, N.,Shiratori, Y.,Tsukuda, T.
Design and synthesis of 2-amino-6-(1H,3H-benzo[de]isochromen-6-yl)-1,3,5-triazines as novel Hsp90 inhibitors
Bioorg.Med.Chem., 22:892-905, 2014

PubMed Abstract: A novel series of 2-amino-1,3,5-triazines bearing a tricyclic moiety as heat shock protein 90 (Hsp90) inhibitors is described. Molecular design was performed using X-ray cocrystal structures of the lead compound CH5015765 and natural Hsp90 inhibitor geldanamycin with Hsp90. We optimized affinity to Hsp90, in vitro cell growth inhibitory activity, water solubility, and liver microsomal stability of inhibitors and identified CH5138303. This compound showed high binding affinity for N-terminal Hsp90α (Kd=0.52nM) and strong in vitro cell growth inhibition against human cancer cell lines (HCT116 IC50=0.098μM, NCI-N87 IC50=0.066μM) and also displayed high oral bioavailability in mice (F=44.0%) and potent antitumor efficacy in a human NCI-N87 gastric cancer xenograft model (tumor growth inhibition=136%).

PubMed: 24369839
DOI: 10.1016/j.bmc.2013.11.036

実験手法

X-RAY DIFFRACTION (1.3 Å)