6PYE

Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 complexed with NR160

6PYE の概要

• エントリーDOI: 10.2210/pdb6pye/pdb
• 分子名称: Hdac6 protein, N-[(1-benzyl-1H-tetrazol-5-yl)methyl]-N-{[4-(hydroxycarbamoyl)phenyl]methyl}-2-(trifluoromethyl)benzamide, 1,2-ETHANEDIOL, ... (6 entities in total)
• 機能のキーワード: histone deacetylase, metallohydrolase, hydrolase
• 由来する生物種: Danio rerio (Zebrafish)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 82313.59

構造登録者

Osko, J.D.,Christianson, D.W. (登録日: 2019-07-29, 公開日: 2020-07-29, 最終更新日: 2023-10-11)

主引用文献

Ressing, N.,Sonnichsen, M.,Osko, J.D.,Scholer, A.,Schliehe-Diecks, J.,Skerhut, A.,Borkhardt, A.,Hauer, J.,Kassack, M.U.,Christianson, D.W.,Bhatia, S.,Hansen, F.K.
Multicomponent Synthesis, Binding Mode, and Structure-Activity Relationship of Selective Histone Deacetylase 6 (HDAC6) Inhibitors with Bifurcated Capping Groups.
J.Med.Chem., 63:10339-10351, 2020

PubMed Abstract: Histone deacetylase 6 (HDAC6) is an emerging target for the treatment of cancer, neurodegenerative diseases, inflammation, and other diseases. Here, we present the multicomponent synthesis and structure-activity relationship of a series of tetrazole-based HDAC6 inhibitors. We discovered the hit compound NR-160 by investigating the inhibition of recombinant HDAC enzymes and protein acetylation. A cocrystal structure of HDAC6 complexed with NR-160 disclosed that the steric complementarity of the bifurcated capping group of NR-160 to the L1 and L2 loop pockets may be responsible for its HDAC6-selective inhibition. While NR-160 displayed only low cytotoxicity as a single agent against leukemia cell lines, it augmented the apoptosis induction of the proteasome inhibitor bortezomib in combination experiments significantly. Furthermore, a combinatorial high-throughput drug screen revealed significantly enhanced cytotoxicity when NR-160 was used in combination with epirubicin and daunorubicin. The synergistic effect in combination with bortezomib and anthracyclines highlights the potential of NR-160 in combination therapies.

PubMed: 32803970
DOI: 10.1021/acs.jmedchem.9b01888

実験手法

X-RAY DIFFRACTION (1.48000295888 Å)