Elucidation of the Histone Deacetylase 6 Pharmacophore

With the FDA approval of suberoylanilide hydroxamic acid (2006) and romidepsin (2009) for the treatment of cutaneous T cell lymphoma, histone deacetylase inhibitors have become the focus of numerous drug discovery efforts both in academia and in the private sector. Inhibition of one isoform in particular, HDAC6, has been demonstrated to provide significant therapeutic benefits in models of neurodegenerative diseases, autoimmune disorders and cancer as well as a variety of other disease states. The work outlined in this dissertation was oriented toward determining the structural features necessary to confer potent and selective HDAC6 inhibition as well as further elucidating the pharmaceutical potential thereof. This was accomplished through the design and synthesis of specific scaffolds each comprising different structural motifs according to the canonical structure of an HDAC inhibitor: cap, linker and zinc binding group. With the desired compounds in hand, we evaluated their activity both in vitro and in vivo. We found that the use of substituted mercaptoacetamide zinc binding groups in place of the traditional hydroxamic acids could provide similar potency at HDAC6. These compounds displayed moderate HDAC6 selectivity and were demonstrated to provide significant neuroprotective benefits in neuronal models of oxidative stress. We also found that substitutions to the 2-position of both β- and γ-carboline cap group derivatives were desirable for selective HDAC6 inhibition. Some of these carboline derivatives exhibited subnanomolar potency at HDAC6 and more than 7,000 fold selectivity for HDAC6 compared to HDAC1. In addition, the use of indole or substituted monoaryl based cap groups provided similar HDAC6 potency and selectivity. These compounds were found to enhance the immunosuppressive function of regulatory T cells both in vitro and in vivo. We also found that a number of the indole and substituted monoaryl based derivatives protected cortical neurons from oxidative stress-induced cell death. The growing interest in selective HDAC inhibitors provides a testament to the scientific significance of these results and suggests that further investigation into the therapeutic use of selective HDAC inhibitors is warranted.