7D1V

Hsp90 alpha N-terminal domain in complex with a 6C compund

7D1V の概要

• エントリーDOI: 10.2210/pdb7d1v/pdb
• 分子名称: Heat shock protein HSP 90-alpha, 6-chloranyl-9-[(3-propan-2-yl-1,2-oxazol-5-yl)methyl]purin-2-amine (3 entities in total)
• 機能のキーワード: chaperone-inhibitor complex, chaperone/inhibitor
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 24694.72

構造登録者

Shin, S.C.,Kim, E.E. (登録日: 2020-09-15, 公開日: 2021-07-28, 最終更新日: 2023-11-29)

主引用文献

Shin, S.C.,El-Damasy, A.K.,Lee, J.H.,Seo, S.H.,Kim, J.H.,Seo, Y.H.,Lee, Y.,Yu, J.H.,Bang, E.K.,Kim, E.E.,Keum, G.
Structural Basis for Design of New Purine-Based Inhibitors Targeting the Hydrophobic Binding Pocket of Hsp90.
Int J Mol Sci, 21:-, 2020

PubMed Abstract: Inhibition of the molecular chaperone heat shock protein 90 (Hsp90) represents a promising approach for cancer treatment. BIIB021 is a highly potent Hsp90 inhibitor with remarkable anticancer activity; however, its clinical application is limited by lack of potency and response. In this study, we aimed to investigate the impact of replacing the hydrophobic moiety of BIIB021, 4-methoxy-3,5-dimethylpyridine, with various five-membered ring structures on the binding to Hsp90. A focused array of /-substituted purines, featuring aromatic and non-aromatic rings, was designed, considering the size of hydrophobic pocket B in Hsp90 to obtain insights into their binding modes within the ATP binding site of Hsp90 in terms of π-π stacking interactions in pocket B as well as outer α-helix 4 configurations. The target molecules were synthesized and evaluated for their Hsp90α inhibitory activity in cell-free assays. Among the tested compounds, the isoxazole derivatives and , and the sole six-membered derivative showed favorable Hsp90α inhibitory activity, with IC values of 1.76 µM, 0.203 µM, and 1.00 µM, respectively. Furthermore, compound 14 elicited promising anticancer activity against MCF-7, SK-BR-3, and HCT116 cell lines. The X-ray structures of compounds , , , , and bound to the -terminal domain of Hsp90 were determined in order to understand the obtained results and to acquire additional structural insights, which might enable further optimization of BIIB021.

PubMed: 33317068
DOI: 10.3390/ijms21249377

実験手法

X-RAY DIFFRACTION (1.332 Å)