9dm6

Crystal Structure of Danio rerio histone deacetylase 6 catalytic domain 2 complexed with an ethylhydrazide inhibitor

spinqualitylabelsall models 9dm6, resolution 1.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9dm6 is a 4 chain structure with sequence from Danio rerio. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.4Å Ligands: A1A6L, EDO, K, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A7YT55_DANRE Publication Abstract from PubMed In this work, we synthesized a series of peptoid-based histone deacetylase (HDAC) inhibitors with variations in the linker region and zinc-binding groups. All compounds were investigated for their HDAC inhibition, antiplasmodial activity, and cytotoxicity against native and cisplatin-resistant carcinoma cell lines. The ethylhydrazide 20 (DS-103) proved to be the most effective compound in these primary screenings. DS-103 showed nanomolar inhibition of class I HDACs and of HDAC6 (class IIb). To further investigate the binding mode of DS-103, a crystal structure of DS-103 in complex with HDAC6 was obtained, which represents the first reported crystal structure of an alkylhydrazide in complex with an HDAC enzyme. Importantly, DS-103 completely reversed cisplatin resistance in two different platinum-resistant solid cancer cell lines and demonstrated strong synergism with cisplatin. The synergistic anticancer effects are mediated by increased DNA damage and p21 expression, resulting in caspase-mediated apoptosis and cell death. Exploring Alternative Zinc-Binding Groups in Histone Deacetylase (HDAC) Inhibitors Uncovers DS-103 as a Potent Ethylhydrazide-Based HDAC Inhibitor with Chemosensitizing Properties.,Stopper D, Biermann L, Watson PR, Li J, Konig B, Gaynes MN, Pessanha de Carvalho L, Klose J, Hanl M, Hamacher A, Schaker-Hubner L, Ramsbeck D, Held J, Christianson DW, Kassack MU, Hansen FK J Med Chem. 2025 Feb 13. doi: 10.1021/acs.jmedchem.4c02373. PMID:39946728 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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