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 may include nausea, vomiting, diarrhea and anorexia; thrombocytopenia (loss of blood platelets responsible for clotting); and profound fatigue. During clinical development, some 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 to harness effectiveness of HDAC inhibition with reduced side effects, and an improved therapeutic profile that will lead to enhanced outcomes for patients.
Acetylon believes that HDAC inhibitor drugs currently on the market or in clinical development achieve their therapeutic impact versus multiple myeloma and other hematologic cancers in part via inhibition of the Class IIb enzyme HDAC6. Inhibition of HDAC6, one of 11 zinc-dependent HDAC enzymes in human cells, blocks a specific protein degradation pathway in cells and, in parallel, increases the proportion of misfolding for new proteins. The resultant accumulation of excess protein in malignant cells triggers programmed cell death, called apoptosis, with little or no effect on normal cells.
Selective inhibition of HDAC6 is expected to reduce or eliminate these often-severe side effects associated with non-selective HDAC inhibition and may enable the development of optimized treatment regimens, including maximally effective combination drug therapies. Indeed, animals lacking the HDAC6 gene have been shown to be fully viable and live normal life spans. Acetylon’s lead drug candidate, ricolinostat (ACY-1215), provides enhanced HDAC6 selectivity versus Class I enzyme isoforms and has demonstrated in preclinical disease models of multiple myeloma and in toxicology testing both excellent disease response and evidence of superior safety versus current alternatives.