Research Projects

Histone deacetylases (HDACs) are a family of zinc-dependent hydrolases that regulate gene expression and enzymatic activity. They have been extensively studied due to their role in cancer pathogenesis and the potential of small-molecule HDAC inhibitors (HDACi). HDACs can be divided into three classes, Class I, II, and IV, consisting of eleven mammalian HDACs. These HDACs have been identified as potential therapeutic targets to reverse aberrant epigenetic modification associated with cancer. However, the design of isoform-specific inhibitors remains a challenge. Most reported HDACs are either class-selective or not selective, causing adverse side effects by inhibiting undesired HDACs or non-HDAC targets. Therefore, there is a pressing need for the development of isoform-specific HDACi. The proposed research aims to develop isoform-specific lysine-based HDACi using a novel high-throughput strategy built on a fluorous platform. The zinc-binding group (ZBG) of HDACi will also be explored to achieve isoform-specificity. Hydroxamates, commonly used as ZBG in HDACs, will be explored for their strong chelation property but suffer from poor pharmacokinetics and non-selective binding to other zinc-dependent enzymes. The promising HDACi will be tested in different cancer cell lines, using a multidisciplinary approach from high-throughput synthesis to mammalian cell culture. Results from these studies will help better understand the function of individual isoforms and provide therapeutic agents with potentially fewer adverse effects by minimizing off-targets.