View source for 9ggk


==Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 (CD2) in complex with N-((6-(Hydroxyamino)-6-oxohexyl)oxy)-4-(4-methoxyphenyl)thiazole-2-carboxamide==
<StructureSection load='9ggk' size='340' side='right'caption='[[9ggk]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9ggk]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Danio_rerio Danio rerio]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9GGK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9GGK FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1IK2:4-(4-methoxyphenyl)-~{N}-[6-(oxidanylamino)-6-oxidanylidene-hexoxy]-1,3-thiazole-2-carboxamide'>A1IK2</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9ggk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9ggk OCA], [https://pdbe.org/9ggk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9ggk RCSB], [https://www.ebi.ac.uk/pdbsum/9ggk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9ggk ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/F8W4B7_DANRE F8W4B7_DANRE] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Histone deacetylase inhibitors (HDACi) are established anticancer drugs, especially in hematological cancers. This study aimed to design, synthesize, and evaluate a set of HDACi featuring a pentyloxyamide connecting unit linker region and substituted phenylthiazole cap groups. A structural optimization program yielded HDACi with nanomolar inhibitory activity against histone deacetylase class I/IIb enzymes. The novel inhibitors (4d and 4m) showed superior antileukemic activity compared to several approved HDACi. Furthermore, 4d and 4m displayed synergistic activity when combined with chemotherapeutics, decitabine, and clofarabine. In vitro pharmacokinetic studies showed the most promising profile for 4d with intermediate microsomal stability, excellent plasma stability, and concentration-independent plasma protein binding. Additionally, 4d demonstrated comparable in vivo pharmacokinetics to vorinostat. When administered in vivo, 4d effectively inhibited the proliferation of leukemia cells without causing toxicity. Furthermore, the binding modes of 4d and 4m to the catalytic domain 2 of HDAC6 from Danio rerio were determined by X-ray crystallography.

Deciphering the Therapeutic Potential of Novel Pentyloxyamide-Based Class I, IIb HDAC Inhibitors against Therapy-Resistant Leukemia.,Fischer F, Schliehe-Diecks J, Tu JW, Gangnus T, Ho YL, Hebeis M, Alves Avelar LA, Scharov K, Watrin T, Kemkes M, Stachura P, Daugs K, Biermann L, Kremeyer J, Horstick N, Span I, Pandyra AA, Borkhardt A, Gohlke H, Kassack MU, Burckhardt BB, Bhatia S, Kurz T J Med Chem. 2024 Nov 27. doi: 10.1021/acs.jmedchem.4c02024. PMID:39602240<ref>PMID:39602240</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9ggk" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Danio rerio]]
[[Category: Large Structures]]
[[Category: Fischer F]]
[[Category: Hebeis M]]
[[Category: Kurz T]]
[[Category: Span I]]