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
This is a non-PDB format compatible entry.
Summary for 9GGK
| Entry DOI | 10.2210/pdb9ggk/pdb |
| Descriptor | Histone deacetylase 6, 4-(4-methoxyphenyl)-~{N}-[6-(oxidanylamino)-6-oxidanylidene-hexoxy]-1,3-thiazole-2-carboxamide, ZINC ION, ... (4 entities in total) |
| Functional Keywords | histone deacetylase, zinc enzyme, inhibitor, hydrolase |
| Biological source | Danio rerio (zebrafish) |
| Total number of polymer chains | 1 |
| Total formula weight | 40926.55 |
| Authors | Hebeis, M.,Fischer, F.,Kurz, T.,Span, I. (deposition date: 2024-08-13, release date: 2024-12-11, Last modification date: 2024-12-25) |
| Primary citation | Fischer, F.,Schliehe-Diecks, J.,Tu, J.W.,Gangnus, T.,Ho, Y.L.,Hebeis, M.,Alves Avelar, L.A.,Scharov, K.,Watrin, T.,Kemkes, M.,Stachura, P.,Daugs, K.,Biermann, L.,Kremeyer, J.,Horstick, N.,Span, I.,Pandyra, A.A.,Borkhardt, A.,Gohlke, H.,Kassack, M.U.,Burckhardt, B.B.,Bhatia, S.,Kurz, T. Deciphering the Therapeutic Potential of Novel Pentyloxyamide-Based Class I, IIb HDAC Inhibitors against Therapy-Resistant Leukemia. J.Med.Chem., 67:21223-21250, 2024 Cited by PubMed Abstract: 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 ( and ) showed superior antileukemic activity compared to several approved HDACi. Furthermore, and displayed synergistic activity when combined with chemotherapeutics, decitabine, and clofarabine. In vitro pharmacokinetic studies showed the most promising profile for with intermediate microsomal stability, excellent plasma stability, and concentration-independent plasma protein binding. Additionally, demonstrated comparable in vivo pharmacokinetics to vorinostat. When administered in vivo, effectively inhibited the proliferation of leukemia cells without causing toxicity. Furthermore, the binding modes of and to the catalytic domain 2 of HDAC6 from were determined by X-ray crystallography. PubMed: 39602240DOI: 10.1021/acs.jmedchem.4c02024 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
Download full validation report
