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
