Searching for Selective Inhibitors of different classes of HDAC

Mentors: Melissa Kemp, Roodolph St. Pierre, Angela Koehler

In chromatin, inside eukaryotic cells, DNA is wrapped around proteins called histones. Histone deacetylases (HDACs) can remove acetyl groups from the lysine tails of histones, making DNA coil more tightly around the histones, preventing transcription. HDACs are involved in many biological functions, and have been linked with various diseases, including cancer, cystic fibrosis, and colitis.

Max’s goal was to evaluate potentially selective class IIa HDAC inhibitors, in both biochemical and cellular acetylation assays, to confirm hits from a previous small molecule microarray experiment for HDAC inhibitors. Max profiled the 28 hit compounds against HDACs 1 through 9, in a biochemical assay for HDAC inhibition. Three compounds were found to be fairly specific inhibitors of HDAC5 (a class IIa HDAC). The cellular acetylation assay Max performed, using the class lla inhibitor and its analogs, resulted in different cellular morphologies and toxicity for some compounds. Other compounds tested, however, showed promising increases in acetylated tubulin levels, in cells treated with these novel HDAC inhibitors.



Max, a senior at Thayer Academy, identified chemicals that selectively inhibit different HDAC enzymes, which influence the winding and packaging of DNA, and have been linked to various human diseases.