4LWE

Crystal Structure of the human Hsp90-alpha N-domain bound to the hsp90 inhibitor FJ2

4LWE の概要

• エントリーDOI: 10.2210/pdb4lwe/pdb
• 関連するPDBエントリー: 4LWF 4LWG 4LWH 4LWI
• 分子名称: Heat shock protein HSP 90-alpha, N-[3-(5-chloro-2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)-1,2-oxazol-5-yl]acetamide (3 entities in total)
• 機能のキーワード: rossmann fold, atp binding, molecularchaperone, chaperone
• 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: 1
• 化学式量合計: 23638.18

構造登録者

Li, J.,Shi, F.,Xiong, B.,He, J. (登録日: 2013-07-27, 公開日: 2014-07-30, 最終更新日: 2023-11-08)

主引用文献

Chen, D.,Shen, A.,Li, J.,Shi, F.,Chen, W.,Ren, J.,Liu, H.,Xu, Y.,Wang, X.,Yang, X.,Sun, Y.,Yang, M.,He, J.,Wang, Y.,Zhang, L.,Huang, M.,Geng, M.,Xiong, B.,Shen, J.
Discovery of potent N-(isoxazol-5-yl)amides as HSP90 inhibitors.
Eur.J.Med.Chem., 87:765-781, 2014

PubMed Abstract: HSP90 is ubiquitously overexpressed in a broad spectrum of human cancers and has been recognized as an attractive target for cancer treatment. Here, we described the fragment screening, synthesis and structure-activity relationship studies of small molecule inhibitors with 4,5-diarylisoxazole scaffold targeting HSP90. Among them, the compound N-(3-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((4-morpholinopiperidin-1-yl)methyl)phenyl)isoxazol-5-yl)cyclopropanecarboxamide (108) showed high affinity for binding to HSP90 (FP binding assay, IC50 = 0.030 μM) and inhibited the proliferation of various human cancer cell lines with averaging GI50 about 88 nM. Compound 108 exhibited its functional inhibition of HSP90 by depleting key signaling pathways and concomitantly elevating of HSP70 and HSP27 in U-87MG cells. Further in vivo studies showed that compound 108 strongly suppressed the tumor growth of human glioblastoma xenograft model U-87MG with T/C = 18.35% at 50 mg/kg q3w/2.5w. Moreover, compound 108 also exhibited good pharmacokinetic properties. Together, our study implicates that compound 108 is a promising candidate of HSP90 inhibitor and is currently advanced to preclinical study.

PubMed: 25313505
DOI: 10.1016/j.ejmech.2014.09.065

実験手法

X-RAY DIFFRACTION (1.5 Å)