Histone deacetylases comprise a family of 18 related enzyme molecules found in most human cells.  11 of these enzymes, also referred to as HDACs, utilize zinc atoms to perform their catalytic activity, the removal of acetyl groups from intracellular proteins. 

Histone proteins are closely associated with the double-helix strands of DNA in the nucleus of a cell.  Acetylation of histones causes structural changes in the DNA-histone complex (“chromatin”) resulting in altered rates of DNA transcription and protein synthesis in cells.  Chemical inhibition of Class I HDACs, which target histones, results in the hyperacetylation of histones causing dysregulated gene expression.

Class I HDAC inhibitors including the drugs and drug candidates vorinostat (Zolinza, Merck), romidepsin (Istodax, Celgene), entinostat (Syndax), panobinostat (Novartis) and others have demonstrated effectiveness in oncology, but they also exhibit substantial adverse side effects in patients, presumably also due to the broad dysregulation of gene expression in normal cells as well as in cancer cells.  Such side effects include nausea, vomiting, diarrhea and anorexia; thrombocytopenia (loss of blood platelets responsible for clotting); and profound fatigue.  During clinical development, Class I HDAC inhibitors have also demonstrated cardiac toxicity related to QT prolongation, including in some instances a propensity for torsades de pointes (profound arrhythmia) and sudden cardiac death. Acetylon is focused on the selective inhibition of key Class II HDAC inhibitor targets, harnessing the proven effectiveness of HDAC inhibition with reduced side effects and an improved therapeutic profile.