Garcinol Is an HDAC11 Inhibitor.

Garcinol is a natural product from the Garcinia Indica fruit and is well-known as an antioxidant, anti-inflammatory, and anticancer agent. However, the understanding of its mechanism of action is still incomplete. It has been reported to be a histone acetyltransferase (HAT) inhibitor. Here, we surprisingly found that garcinol is a potent histone deacetylase 11 (HDAC11) inhibitor (IC50 ∼ 5 µM in vitro with the HPLC assay and IC50 ∼ 10 µM in the cellular SHMT2 fatty acylation assay), which is comparable to previously reported HDAC11 inhibitors. Additionally, among all the HDACs tested, garcinol specifically inhibits HDAC11 over other HDACs. HDAC11 is the only class IV HDAC, and there are very few inhibitors available for it. Therefore, this study provides a new HDAC11 inhibitor lead from natural products and may help explain the various biological activities of garcinol.

Activity-Guided Design of HDAC11-Specific Inhibitors.

Mammalian histone deacetylases (HDACs) are a class of enzymes that play important roles in biological pathways. Existing HDAC inhibitors target multiple HDACs without much selectivity. Inhibitors that target one particular HDAC will be useful for investigating the biological functions of HDACs and for developing better therapeutics. Here, we report the development of HDAC11-specific inhibitors using an activity-guided rational design approach. The enzymatic activity and biological function of HDAC11 have been little known, but recent reports suggest that it has efficient defatty-acylation activity and that inhibiting it could be useful for treating a variety of human diseases, including viral infection, multiple sclerosis, and metabolic diseases. Our best inhibitor, SIS17, is active in cells and inhibited the demyristoylation of a known HDAC11 substrate, serine hydroxymethyl transferase 2, without inhibiting other HDACs. The activity-guided design may also be useful for the development of isoform-specific inhibitors for other classes of enzymes.