9DM6

Crystal Structure of Danio rerio histone deacetylase 6 catalytic domain 2 complexed with an ethylhydrazide inhibitor

これはPDB形式変換不可エントリーです。

9DM6 の概要

• エントリーDOI: 10.2210/pdb9dm6/pdb
• 分子名称: Hdac6 protein, N-[2-(benzylamino)-2-oxoethyl]-4-(dimethylamino)-N-{[4-(2-ethylhydrazine-1-carbonyl)phenyl]methyl}benzamide, 1,2-ETHANEDIOL, ... (6 entities in total)
• 機能のキーワード: hydrolase, histone deacetylase, inhibitor, metallohydrolase
• 由来する生物種: Danio rerio (zebrafish)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 164473.61

構造登録者

Gaynes, M.N.,Watson, P.R.,Konig, B.,Christianson, D.W. (登録日: 2024-09-12, 公開日: 2025-02-26, 最終更新日: 2025-03-12)

主引用文献

Stopper, D.,Biermann, L.,Watson, P.R.,Li, J.,Konig, B.,Gaynes, M.N.,Pessanha de Carvalho, L.,Klose, J.,Hanl, M.,Hamacher, A.,Schaker-Hubner, L.,Ramsbeck, D.,Held, J.,Christianson, D.W.,Kassack, M.U.,Hansen, F.K.
Exploring Alternative Zinc-Binding Groups in Histone Deacetylase (HDAC) Inhibitors Uncovers DS-103 as a Potent Ethylhydrazide-Based HDAC Inhibitor with Chemosensitizing Properties.
J.Med.Chem., 68:4426-4452, 2025

PubMed Abstract: In this work, we synthesized a series of peptoid-based histone deacetylase (HDAC) inhibitors with variations in the linker region and zinc-binding groups. All compounds were investigated for their HDAC inhibition, antiplasmodial activity, and cytotoxicity against native and cisplatin-resistant carcinoma cell lines. The ethylhydrazide () proved to be the most effective compound in these primary screenings. showed nanomolar inhibition of class I HDACs and of HDAC6 (class IIb). To further investigate the binding mode of , a crystal structure of in complex with HDAC6 was obtained, which represents the first reported crystal structure of an alkylhydrazide in complex with an HDAC enzyme. Importantly, completely reversed cisplatin resistance in two different platinum-resistant solid cancer cell lines and demonstrated strong synergism with cisplatin. The synergistic anticancer effects are mediated by increased DNA damage and p21 expression, resulting in caspase-mediated apoptosis and cell death.

PubMed: 39946728
DOI: 10.1021/acs.jmedchem.4c02373

実験手法

X-RAY DIFFRACTION (1.4 Å)