Discovery of a New Isoxazole-3-hydroxamate-Based Histone Deacetylase 6 Inhibitor SS-208 with Antitumor Activity in Syngeneic Melanoma Mouse Models
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem
Grantová podpora
R21 CA184612
NCI NIH HHS - United States
R01 NS079183
NINDS NIH HHS - United States
R43 HD093464
NICHD NIH HHS - United States
R41 AG058283
NIA NIH HHS - United States
- MeSH
- CD8-pozitivní T-lymfocyty cytologie MeSH
- dánio pruhované MeSH
- histondeacetylasa 6 antagonisté a inhibitory MeSH
- inhibitory histondeacetylas chemie farmakologie MeSH
- isoxazoly chemie farmakologie MeSH
- katalytická doména MeSH
- kyseliny hydroxamové chemie farmakologie MeSH
- lidé MeSH
- makrofágy cytologie MeSH
- melanom farmakoterapie MeSH
- mikrozomy chemie MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- NKT buňky cytologie MeSH
- objevování léků MeSH
- transplantace izogenní MeSH
- zinek chemie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- HDAC6 protein, human MeSH Prohlížeč
- Hdac6 protein, mouse MeSH Prohlížeč
- histondeacetylasa 6 MeSH
- inhibitory histondeacetylas MeSH
- isoxazoly MeSH
- kyseliny hydroxamové MeSH
- zinek MeSH
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
Promega Corporation Madison Wisconsin 53711 United States
StarWise Therapeutics LLC University Research Park Inc Madison Wisconsin 53719 United States
Citace poskytuje Crossref.org
