Competitive or noncompetitive, that's the question: research toward histone deacetylase inhibitors.

Histone deacetylase (HDAC) catalyze deacetylation of acetylated lysine residues on histones and a growing number of nonhistone proteins including many transcription factors, playing an important role in the upstream control of gene transcription, cell cycle progression, and apoptosis. It has been wildly recognized that HDACs are promising targets for cancer therapy. At least 10 HDAC inhibitors are currently in clinical evaluation. However, none of them is practically isoform selective. More and more evidence suggests that acetylation modification occurring in approximately 85% of eukaryotic proteins should be a general mechanism for altering protein structures or protein-protein interactions. Unselectively inhibiting the deacetylation activity of HDACs and the consequent modulation of the acetylation status of so many substrates might have multiple mechanisms of action in vivo, resulting in both therapeutic responses and unanticipated side effects. Lack of selectivity for the existing HDAC inhibitors is somewhat logical for the highly conserved residues in the catalytic site and the malleable structure in the rim of the active site of HDAC enzymes. For further advancements in the development of HDAC inhibitors, clues for selectivity will have to be considered.