Discovery of a New Isoxazole-3-hydroxamate-Based Histone Deacetylase 6 Inhibitor SS-208 with Antitumor Activity in Syngeneic Melanoma Mouse Models

0510398 - BTÚ 2020 RIV US eng J - Journal Article
Shen, S. - Hadley, M. - Ustinova, Kseniya - Pavlíček, Jiří - Knox, T. - Noonepalle, S. - Tavares, M. T. - Zimprich, Ch. A. - Zhang, A. - Robers, M. B. - Bařinka, Cyril - 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.
Journal of Medicinal Chemistry. Roč. 62, č. 18 (2019), s. 8557-8577. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA ČR GA15-19640S; GA MŠMT(CZ) LM2015043; GA MŠMT(CZ) ED1.1.00/02.0109
Institutional support: RVO:86652036
Keywords : HDAC6-SELECTIVE INHIBITORS * ACQUIRED-RESISTANCE * HDAC6 INHIBITOR
OECD category: Pharmacology and pharmacy
Impact factor: 6.205, year: 2019
Method of publishing: Open access
https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b00946

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 Danio rerio 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.
Permanent Link: http://hdl.handle.net/11104/0300905