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.

Bontac Bio Engineering Co Ltd Shenzhen Guangdong 518102 China

Department of Biochemistry and Molecular Medicine The George Washington University Washington District of Columbia 20052 United States

Department of Medicinal Chemistry and Pharmacognosy College of Pharmacy University of Illinois at Chicago Chicago Illinois 60612 United States

Laboratory of Structural Biology Institute of Biotechnology of the Czech Academy of Sciences Prumyslova 595 252 50 Vestec Czech Republic

Laboratory of Structural Biology Institute of Biotechnology of the Czech Academy of Sciences Prumyslova 595 252 50 Vestec Czech Republic Department of Biochemistry Faculty of Natural Science Charles University Albertov 6 128 43 Prague 2 Czech Republic

Promega Corporation Madison Wisconsin 53711 United States

StarWise Therapeutics LLC University Research Park Inc Madison Wisconsin 53719 United States

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$a Shen, Sida $u Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy , University of Illinois at Chicago , Chicago , Illinois 60612 , United States.

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$a Discovery of a New Isoxazole-3-hydroxamate-Based Histone Deacetylase 6 Inhibitor SS-208 with Antitumor Activity in Syngeneic Melanoma Mouse Models / $c S. Shen, M. Hadley, K. Ustinova, J. Pavlicek, T. Knox, S. Noonepalle, MT. Tavares, CA. Zimprich, G. Zhang, MB. Robers, C. Bařinka, AP. Kozikowski, A. Villagra,

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$a 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.

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$a Hadley, Melissa $u Department of Biochemistry and Molecular Medicine , The George Washington University , Washington, District of Columbia 20052 , United States.

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$a Ustinova, Kseniya $u Laboratory of Structural Biology , Institute of Biotechnology of the Czech Academy of Sciences , Prumyslova 595 , 252 50 Vestec , Czech Republic. Department of Biochemistry, Faculty of Natural Science , Charles University , Albertov 6 , 128 43 Prague 2 , Czech Republic.

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$a Pavlicek, Jiri $u Laboratory of Structural Biology , Institute of Biotechnology of the Czech Academy of Sciences , Prumyslova 595 , 252 50 Vestec , Czech Republic.

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$a Knox, Tessa $u Department of Biochemistry and Molecular Medicine , The George Washington University , Washington, District of Columbia 20052 , United States.

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$a Noonepalle, Satish $u Department of Biochemistry and Molecular Medicine , The George Washington University , Washington, District of Columbia 20052 , United States.

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$a Bařinka, Cyril $u Laboratory of Structural Biology , Institute of Biotechnology of the Czech Academy of Sciences , Prumyslova 595 , 252 50 Vestec , Czech Republic.

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$a Kozikowski, Alan P $u StarWise Therapeutics LLC, University Research Park, Inc. , Madison , Wisconsin 53719 , United States.

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$a Villagra, Alejandro $u Department of Biochemistry and Molecular Medicine , The George Washington University , Washington, District of Columbia 20052 , United States.

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