Rational Design of Suprastat: A Novel Selective Histone Deacetylase 6 Inhibitor with the Ability to Potentiate Immunotherapy in Melanoma Models

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.