Telling enzymes to Shh

A chemical probe that inhibits the enzyme Hedgehog acetyltransferase (Hhat) in cells is reported this week in Nature Chemical Biology. The discovery of this small molecule inhibitor may serve as a lead for drug discovery efforts which aim to validate Hhat as a viable therapeutic target in cancer.

Sonic hedgehog (Shh) signaling is important for normal embryonic development whereas abnormal Shh signaling contributes to many kinds of cancer. Shh is a protein that undergoes several chemical modifications before it is activated and secreted from a cell. One of these modifications depends on the enzyme Hhat, which attaches a palmitate or lipid to the protein. No inhibitors of this enzyme have previously been reported.

Marilyn Resh and colleagues report a potent inhibitor of Hhat called RU-SKI 43, identified in a high-throughput screen. RU-SKI 43 inhibits the enzyme in cells and is selective for Hhat over other related enzymes. The identification of this small molecule inhibitor will allow scientists to investigate the importance of this enzyme in the regulation of Shh activity.