Selective inhibition of histone deacetylase 6 (HDAC6) is being recognized as a therapeutic approach for cancers. In this study, we designed a new HDAC6 inhibitor, named Suprastat, using in silico simulations. X-ray crystallography and molecular dynamics simulations provide strong evidence to support the notion that the aminomethyl and hydroxyl groups in the capping group of Suprastat establish significant hydrogen bond interactions, either direct or water-mediated, with residues D460, N530, and S531, which play a vital role in regulating the deacetylase function of the enzyme and which are absent in other isoforms. In vitro characterization of Suprastat demonstrates subnanomolar HDAC6 inhibitory potency and a hundred- to a thousand-fold HDAC6 selectivity over the other HDAC isoforms. In vivo studies reveal that a combination of Suprastat and anti-PD1 immunotherapy enhances antitumor immune response, mediated by a decrease of protumoral M2 macrophages and increased infiltration of antitumor CD8+ effector and memory T-cells.

• MeSH
• fenylmočovinové sloučeniny chemická syntéza   metabolismus   terapeutické užití   MeSH
• histondeacetylasa 6 antagonisté a inhibitory   metabolismus   MeSH
• imunologické faktory chemická syntéza   metabolismus   terapeutické užití   MeSH
• imunoterapie MeSH
• inhibitory histondeacetylas chemická syntéza   metabolismus   terapeutické užití   MeSH
• jaterní mikrozomy metabolismus   MeSH
• krysa rodu rattus MeSH
• krystalografie rentgenová MeSH
• kyseliny hydroxamové chemická syntéza   metabolismus   terapeutické užití   MeSH
• lidé MeSH
• melanom farmakoterapie   terapie   MeSH
• myši inbrední C57BL MeSH
• nádorové buněčné linie MeSH
• racionální návrh léčiv MeSH
• simulace molekulární dynamiky MeSH
• vazba proteinů MeSH
• vodíková vazba MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural 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.

• 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