6VNR

Crystal Structure of Danio rerio Histone Deacetylase 6 Catalytic Domain 2 (CD2) Complexed with Bishydroxamic Acid Inhibitor

6VNR の概要

• エントリーDOI: 10.2210/pdb6vnr/pdb
• 分子名称: Hdac6 protein, ZINC ION, POTASSIUM ION, ... (6 entities in total)
• 機能のキーワード: histone deacetylase, metallohydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 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: 81632.95

構造登録者

Osko, J.D.,Porter, N.J.,Christianson, D.W. (登録日: 2020-01-29, 公開日: 2020-05-13, 最終更新日: 2023-10-11)

主引用文献

Morgen, M.,Steimbach, R.R.,Geraldy, M.,Hellweg, L.,Sehr, P.,Ridinger, J.,Witt, O.,Oehme, I.,Herbst-Gervasoni, C.J.,Osko, J.D.,Porter, N.J.,Christianson, D.W.,Gunkel, N.,Miller, A.K.
Design and Synthesis of Dihydroxamic Acids as HDAC6/8/10 Inhibitors.
Chemmedchem, 15:1163-1174, 2020

PubMed Abstract: We report the synthesis and evaluation of a class of selective multitarget agents for the inhibition of HDAC6, HDAC8, and HDAC10. The concept for this study grew out of a structural analysis of the two selective inhibitors Tubastatin A (HDAC6/10) and PCI-34051 (HDAC8), which we recognized share the same N-benzylindole core. Hybridization of the two inhibitor structures resulted in dihydroxamic acids with benzyl-indole and -indazole core motifs. These substances exhibit potent activity against HDAC6, HDAC8, and HDAC10, while retaining selectivity over HDAC1, HDAC2, and HDAC3. The best substance inhibited the viability of the SK-N-BE(2)C neuroblastoma cell line with an IC value similar to a combination treatment with Tubastatin A and PCI-34051. This compound class establishes a proof of concept for such hybrid molecules and could serve as a starting point for the further development of enhanced HDAC6/8/10 inhibitors.

PubMed: 32348628
DOI: 10.1002/cmdc.202000149

実験手法

X-RAY DIFFRACTION (1.94301319072 Å)