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 principally 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. Currently available HDAC drugs non-selectively target multiple HDAC enzymes including those of Class I, resulting in dysregulated expression of numerous genes in normal cells as well as cancer cells. Side effects commonly associated with non-selective HDAC drugs due to Class I HDAC inhibition include gastrointestinal dysfunction, lowered blood platelet levels and risk of hemorrhage, and profound fatigue as well as potential for severe cardiac complications.

Selective inhibition of HDAC6 uniquely preserves normal gene expression in cells, and is therefore 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 for normal life spans.  Acetylon’s lead drug candidate, 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.