Rational Design of Suprastat: A Novel Selective Histone Deacetylase 6 Inhibitor with the Ability to Potentiate Immunotherapy in Melanoma Models
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Grant support
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
- Phenylurea Compounds chemical synthesis metabolism therapeutic use MeSH
- Histone Deacetylase 6 antagonists & inhibitors metabolism MeSH
- Immunologic Factors chemical synthesis metabolism therapeutic use MeSH
- Immunotherapy MeSH
- Histone Deacetylase Inhibitors chemical synthesis metabolism therapeutic use MeSH
- Microsomes, Liver metabolism MeSH
- Rats MeSH
- Crystallography, X-Ray MeSH
- Hydroxamic Acids chemical synthesis metabolism therapeutic use MeSH
- Humans MeSH
- Melanoma drug therapy therapy MeSH
- Mice, Inbred C57BL MeSH
- Cell Line, Tumor MeSH
- Drug Design MeSH
- Molecular Dynamics Simulation MeSH
- Protein Binding MeSH
- Hydrogen Bonding MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Names of Substances
- Phenylurea Compounds MeSH
- HDAC6 protein, human MeSH Browser
- Histone Deacetylase 6 MeSH
- Immunologic Factors MeSH
- Histone Deacetylase Inhibitors MeSH
- Hydroxamic Acids MeSH
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.
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