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
Chimeric antigen receptor anti-CD19 (CAR19)-T cell immunotherapy-induced clinical remissions in CD19+ B cell lymphomas are often short lived. We tested whether CAR19-engineering of the CD1d-restricted invariant natural killer T (iNKT) cells would result in enhanced anti-lymphoma activity. CAR19-iNKT cells co-operatively activated by CD1d- and CAR19-CD19-dependent interactions are more effective than CAR19-T cells against CD1d-expressing lymphomas in vitro and in vivo. The swifter in vivo anti-lymphoma activity of CAR19-iNKT cells and their enhanced ability to eradicate brain lymphomas underpinned an improved tumor-free and overall survival. CD1D transcriptional de-repression by all-trans retinoic acid results in further enhanced cytotoxicity of CAR19-iNKT cells against CD19+ chronic lymphocytic leukemia cells. Thus, iNKT cells are a highly efficient platform for CAR-based immunotherapy of lymphomas and possibly other CD1d-expressing cancers.
- MeSH
- antigeny CD19 genetika imunologie MeSH
- antigeny CD1d genetika imunologie MeSH
- buněčná a tkáňová terapie * MeSH
- chronická lymfatická leukemie genetika imunologie MeSH
- imunoterapie metody MeSH
- lidé MeSH
- lymfom farmakoterapie imunologie MeSH
- myši MeSH
- NKT buňky cytologie imunologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- buňky NK cytologie imunologie MeSH
- interleukin-13 imunologie izolace a purifikace MeSH
- lékařská onkologie metody trendy MeSH
- lidé MeSH
- nádorové procesy MeSH
- nádory imunologie krev MeSH
- NKT buňky cytologie imunologie MeSH
- pilotní projekty MeSH
- průtoková cytometrie metody využití MeSH
- retrospektivní studie MeSH
- T-lymfocyty cytologie imunologie MeSH
- Check Tag
- lidé MeSH