7UK2

Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 complexed with NN-390

Summary for 7UK2

• Entry DOI: 10.2210/pdb7uk2/pdb
• Descriptor: Hdac6 protein, N-hydroxy-4-{[(propan-2-yl)(2,3,4,5-tetrafluorobenzene-1-sulfonyl)amino]methyl}benzamide, ZINC ION, ... (5 entities in total)
• Functional Keywords: potassium ion binding, alkali metal ion binding, ion binding, cation binding, metal ion binding, catalytic activity, hydrolase activity, deacetylase activity, protein deacetylase activity, acting on a protein, acting on carbon-nitrogen (but not peptide) bonds, in linear amides, tubulin deacetylase activity, zinc ion binding, transition metal ion binding, metal binding protein, metal binding protein-inhibitor complex, metal binding protein/inhibitor
• Biological source: Danio rerio (zebrafish)
• Total number of polymer chains: 1
• Total formula weight: 40288.96

Authors

Erdogan, F.,Seo, H.-S.,Dhe-Paganon, S. (deposition date: 2022-03-31, release date: 2022-11-02, Last modification date: 2023-10-25)

Primary citation

Garcha, H.K.,Nawar, N.,Sorger, H.,Erdogan, F.,Aung, M.M.K.,Sedighi, A.,Manaswiyoungkul, P.,Seo, H.S.,Schonefeldt, S.,Poloske, D.,Dhe-Paganon, S.,Neubauer, H.A.,Mustjoki, S.M.,Herling, M.,de Araujo, E.D.,Moriggl, R.,Gunning, P.T.
High Efficacy and Drug Synergy of HDAC6-Selective Inhibitor NN-429 in Natural Killer (NK)/T-Cell Lymphoma.
Pharmaceuticals, 15:-, 2022

PubMed Abstract: NK/T-cell lymphoma (NKTCL) and γδ T-cell non-Hodgkin lymphomas (γδ T-NHL) are highly aggressive lymphomas that lack rationally designed therapies and rely on repurposed chemotherapeutics from other hematological cancers. Histone deacetylases (HDACs) have been targeted in a range of malignancies, including T-cell lymphomas. This study represents exploratory findings of HDAC6 inhibition in NKTCL and γδ T-NHL through a second-generation inhibitor NN-429. With nanomolar in vitro HDAC6 potency and high in vitro and in cellulo selectivity for HDAC6, NN-429 also exhibited long residence time and improved pharmacokinetic properties in contrast to older generation inhibitors. Following unique selective cytotoxicity towards γδ T-NHL and NKTCL, NN-429 demonstrated a synergistic relationship with the clinical agent etoposide and potential synergies with doxorubicin, cytarabine, and SNS-032 in these disease models, opening an avenue for combination treatment strategies.

PubMed: 36355493
DOI: 10.3390/ph15111321

Experimental method

X-RAY DIFFRACTION (1.6 Å)