Histone deacetylase inhibitors: a chemical genetics approach to understanding cellular functions

Abstract

There are eleven zinc dependent histone deacetylases (HDAC) in humans which have histones and many non-histone substrates. The substrates of these enzymes include proteins that have a role in regulation of gene expression, cell proliferation, cell migration, cell death, immune pathways and angiogenesis. Inhibitors of HDACs (HDACi) have been developed which alter the structure and function of these proteins, causing molecular and cellular changes that induce transformed cell death. The HDACi are being developed as anti-cancer drugs and have therapeutic potential for many non-oncologic diseases.

Figure 1

A: Structural features of hydroxamic acid based inhibitors of HDACs (see text for details). B: Schematic representation of the crystal structure of the histone deacetylase-like protein with SAHA (vorinostat) that inserts into the pocket-like catalytic site of the enzyme. At the base of the catalytic pocket is a zinc molecule with which the hydroxamic moiety of SAHA binds (after 35).