6VNQ

Crystal Structure of Danio rerio Histone Deacetylase 10 in Complex with Bishydroxamic Acid Based Inhibitor

Summary for 6VNQ

• Entry DOI: 10.2210/pdb6vnq/pdb
• Descriptor: Polyamine deacetylase HDAC10, N-hydroxy-1-{[4-(hydroxycarbamoyl)phenyl]methyl}-1H-indole-6-carboxamide, 1,2-ETHANEDIOL, ... (7 entities in total)
• Functional Keywords: histone deacetylase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Danio rerio (Zebrafish)
• Total number of polymer chains: 1
• Total formula weight: 75838.64

Authors

Herbst-Gervasoni, C.J.,Christianson, D.W. (deposition date: 2020-01-29, release date: 2020-05-13, Last modification date: 2023-10-11)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.05 Å)