6R0K

X-ray structure of Danio rerio histone deacetylase 6 (HDAC6) CD2 in complex with a inhibitor SS208

Summary for 6R0K

• Entry DOI: 10.2210/pdb6r0k/pdb
• Descriptor: Histone deacetylase 6, ZINC ION, POTASSIUM ION, ... (6 entities in total)
• Functional Keywords: protein deacetylase, histone deacetylase 6, zinc-binding, isoxazole-3-hydroxamate analogues, hydrolase
• Biological source: Danio rerio (Zebrafish)
• Total number of polymer chains: 1
• Total formula weight: 40851.54

Authors

Barinka, C.,Ustinova, K.,Motlova, L.,Pavlicek, J. (deposition date: 2019-03-13, release date: 2019-10-09, Last modification date: 2024-01-24)

Primary citation

Shen, S.,Hadley, M.,Ustinova, K.,Pavlicek, J.,Knox, T.,Noonepalle, S.,Tavares, M.T.,Zimprich, C.A.,Zhang, G.,Robers, M.B.,Barinka, C.,Kozikowski, A.P.,Villagra, A.
Discovery of a New Isoxazole-3-hydroxamate-Based Histone Deacetylase 6 Inhibitor SS-208 with Antitumor Activity in Syngeneic Melanoma Mouse Models.
J.Med.Chem., 62:8557-8577, 2019

PubMed Abstract: Isoxazole is a five-membered heterocycle that is widely used in drug discovery endeavors. Here, we report the design, synthesis, and structural and biological characterization of SS-208, a novel HDAC6-selective inhibitor containing the isoxazole-3-hydroxamate moiety as a zinc-binding group as well as a hydrophobic linker. A crystal structure of the HDAC6/SS-208 complex reveals a bidentate coordination of the active-site zinc ion that differs from the preferred monodentate coordination observed for HDAC6 complexes with phenylhydroxamate-based inhibitors. While SS-208 has minimal effects on the viability of murine SM1 melanoma cells in vitro, it significantly reduced in vivo tumor growth in a murine SM1 syngeneic melanoma mouse model. These findings suggest that the antitumor activity of SS-208 is mainly mediated by immune-related antitumor activity as evidenced by the increased infiltration of CD8+ and NK+ T cells and the enhanced ratio of M1 and M2 macrophages in the tumor microenvironment.

PubMed: 31414801
DOI: 10.1021/acs.jmedchem.9b00946

Experimental method

X-RAY DIFFRACTION (1.15 Å)