Recent Advances in Medicinal Chemistry of Histone Deacetylase Inhibitors

Abstract

Publisher Summary Histone deacetylases (HDACs) inhibitors induce histone hyperacetylation, reactivate suppressed genes and consequently, inhibit the cell cycle, activate differentiation programmes or induce apoptosis and several HDAC inhibitors of various structural families have now advanced into phase I and II clinical trials. Mammalian HDACs can be divided into three distinct classes. Class I deacetylases, HDACs 1, 2, 2, 8, share homology in their catalytic sites with molecular weights of 42–55 kDa. Class II deacetylases includes HDACs with molecular weights between 120–130 kDa. The third class of deacetylases is the conserved Sir2 family of proteins which are dependent on NAD + for activity whereas Class I and II HDACs operate by zinc-dependent mechanisms. HDAC inhibitors bear great potential as new drugs because of their ability to modulate transcription, and are endowed with cytodifferentiating, antiproliferative and apoptogenic properties. Furthermore the anticancer activity of HDAC inhibitors may be mediated in part by the inhibition of angiogenesis, since it was shown recently that TSA specifically inhibited hypoxia-induced angiogenesis by reducing the expression of genes required for angiogenesis. Several structural classes of compounds have been described as HDAC inhibitors. The most important of these compound classes are short-chain fatty acids, hydroxamic acids, benzamides, and cyclic tetrapeptides.