Toward HDAC Isoform-Selective Inhibitors for the Treatment of Cancer and Infectious Diseases

Histone deacetylase (HDAC) proteins are the most studied and characterized erasers of post-translational modifications (PTMs) and play a pivotal role in the epigenetic machinery. HDAC activity and/or expression are dysregulated in disease; therefore, HDACs have emerged as promising therapeutic targets and five HDAC inhibitors have been approved by the Food and Drug Administration (FDA). These inhibitors are nonselective and their clinical outcomes are not optimal, and there is a growing body of preclinical and clinical evidence that the different HDAC isoforms have unique biological functions. This suggests that the efficacy and side effect profile of these inhibitors could be improved by targeting a single HDAC isoform in a specific disease state. In this thesis, rationale for and progress toward development of isoform-selective HDAC inhibitors are presented. First, investigation of the regulation of hepatitis B virus (HBV), a worldwide clinical problem, biosynthesis by class I and II HDACs is conducted and demonstrated an unconventional role of catalytically active HDAC5 in the regulation of HBV biosynthesis. HDAC5 expression increased both the stability and splicing of the HBV 3.5 kb RNA. These observations demonstrate the importance of specifically targeting HDAC5 for HBV therapeutic development and point to a broader role of HDAC5 in regulating RNA splicing and transcript stability. Second, the modeling, design, synthesis, and biological evaluation of a novel series of C1-substituted tetrahydroisoquinoline (TIQ)-based HDAC8 selective inhibitors are described. The cytotoxicity of the most potent and selective compounds was evaluated in neuroblastoma cell lines. Discovery of the novel TIQ chemotype paves the way for the development of HDAC8 selective inhibitors for therapeutic applications. A growing body of evidence, including the data presented in this thesis, demonstrate the many deleterious implications of using currently available nonselective inhibitors as therapies. Collectively, development of isoform-selective HDAC inhibitors could potentially overcome the many limitations of currently available nonselective inhibitors.