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 (IC 50 ∼ 5 μM in vitro with the HPLC assay and IC 50 ∼ 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.

Histone deacetylases (HDACs) are enzymes that regulate many important biological pathways. There is a need for the development of isoform-selective HDAC inhibitors for further biological applications. Here, we report the development of trapoxin A analogues as potent and selective inhibitors of HDAC11, an enzyme that can efficiently remove long-chain fatty acyl groups from proteins. In particular, we show that one of the trapoxin A analogues, TD034, has nanomolar potency in enzymatic assays. We show that in cells, TD034 is active at low micromolar concentrations and inhibits the defatty acylation of SHMT2, a known HDAC11 substrate. The high potency and selectivity of TD034 would permit further development of HDAC11 inhibitors for biological and therapeutic applications.