HDAC Inhibitors and Activators

HDAC8 Selective Inhibitors

Histone Deacetylase is a family of enzymes involved in the regulation of gene transcription. They act by removing the acetate groups off of the lysine residues of histones, thus turning off gene expression. In diseases such as cancer, lupus and Huntington’s disease, the regulation of histone acetylation is out of balance. HDAC inhibitors have been shown to be effective in cancer chemotherapy by allowing tumor suppressor genes to be transcribed. While there is one commercial HDAC inhibitor on the market for the treatment of T-Cell Lymphoma, vorinostat is a broad spectrum HDAC inhibitor and thus possesses many side effects. Our goal is to prepare new inhibitors that will target a specific HDAC involved in a disease. Toward this goal we have discovered several new small molecules that selectivity inhibit HDAC8.

 

HDAC8 Selective Activators

We have synthesized a new compound which increases the activity of HDAC8. Currently there are no small molecule HDAC agonists known and our discovery will provide useful tools for biomedical researchers to ask important questions about the role of HDACs in biology and disease. The compound shown below increases the activity of HDAC8 toward a fluorescent substrate by 12 fold at a concentration of 10 micromolar.

Fluorescently Tagged PAN HDAC Inhibitors

We have prepared an analog of vorinostat with an aminocoumarin tag for mechanistic studies. This compound is a more potent PAN inhibitor than vorinostat.

Protein structure images were rendered using UCSF Chimera. Chimera is developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIGMS P41-GM103311).