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

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. 2019 Sep 26;62(18):8557-8577. doi: 10.1021/acs.jmedchem.9b00946.
Sida Shen 1,  Melissa Hadley 2,  Kseniya Ustinova 3 4,  Jiri Pavlicek 3,  Tessa Knox 2,  Satish Noonepalle 2,  Mauricio T Tavares 1,  Chad A Zimprich 5,  Guiping Zhang 6,  Matthew B Robers 5,  Cyril Bařinka 3,  Alan P Kozikowski 7,  Alejandro Villagra 2
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy , University of Illinois at Chicago , Chicago , Illinois 60612 , United States.
  • 2 Department of Biochemistry and Molecular Medicine , The George Washington University , Washington, District of Columbia 20052 , United States.
  • 3 Laboratory of Structural Biology , Institute of Biotechnology of the Czech Academy of Sciences , Prumyslova 595 , 252 50 Vestec , Czech Republic.
  • 4 Department of Biochemistry, Faculty of Natural Science , Charles University , Albertov 6 , 128 43 Prague 2 , Czech Republic.
  • 5 Promega Corporation , Madison , Wisconsin 53711 , United States.
  • 6 Bontac Bio-Engineering (Shenzhen) Co., Ltd , Shenzhen , Guangdong 518102 , China.
  • 7 StarWise Therapeutics LLC, University Research Park, Inc. , Madison , Wisconsin 53719 , United States.
PMID: 31414801 DOI: 10.1021/acs.jmedchem.9b00946
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 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-126330
    99.00%, HDAC Inhibitor