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Discovery of a New Isoxazole-3-hydroxamate-Based Histone Deacetylase 6 Inhibitor SS-208 with Antitumor Activity in Syngeneic Melanoma Mouse Models
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SYSNO ASEP 0510398 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Discovery of a New Isoxazole-3-hydroxamate-Based Histone Deacetylase 6 Inhibitor SS-208 with Antitumor Activity in Syngeneic Melanoma Mouse Models Author(s) Shen, S. (US)
Hadley, M. (US)
Ustinova, Kseniya (BTO-N)
Pavlíček, Jiří (BTO-N) RID
Knox, T. (US)
Noonepalle, S. (US)
Tavares, M. T. (US)
Zimprich, Ch. A. (US)
Zhang, A. (CN)
Robers, M. B. (US)
Bařinka, Cyril (BTO-N) RID, ORCID
Kozikowski, A. P. (US)
Villagra, A. (US)Number of authors 13 Source Title Journal of Medicinal Chemistry. - : American Chemical Society - ISSN 0022-2623
Roč. 62, č. 18 (2019), s. 8557-8577Number of pages 21 s. Language eng - English Country US - United States Keywords HDAC6-SELECTIVE INHIBITORS ; ACQUIRED-RESISTANCE ; HDAC6 INHIBITOR Subject RIV FR - Pharmacology ; Medidal Chemistry OECD category Pharmacology and pharmacy R&D Projects GA15-19640S GA ČR - Czech Science Foundation (CSF) LM2015043 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) ED1.1.00/02.0109 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support BTO-N - RVO:86652036 UT WOS 000488334500012 EID SCOPUS 85072641509 DOI 10.1021/acs.jmedchem.9b00946 Annotation 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. Workplace Institute of Biotechnology Contact Monika Kopřivová, Monika.Koprivova@ibt.cas.cz, Tel.: 325 873 700 Year of Publishing 2020 Electronic address https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b00946
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